Moxonidine increases uptake of oxidised low-density lipoprotein in cultured vascular smooth muscle cells and inhibits atherosclerosis in apolipoprotein E-deficient mice
- Wang, Yutang, Nguyen, Dinh, Anesi, Jack, Alramahi, Ahmed, Witting, Paul, Chai, Zhonglin, Khan, Abdul, Kelly, Jason, Denton, Kate, Golledge, Jonathan
- Authors: Wang, Yutang , Nguyen, Dinh , Anesi, Jack , Alramahi, Ahmed , Witting, Paul , Chai, Zhonglin , Khan, Abdul , Kelly, Jason , Denton, Kate , Golledge, Jonathan
- Date: 2023
- Type: Text , Journal article
- Relation: International Journal of Molecular Sciences Vol. 24, no. 4 (2023), p.
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: This study aimed to investigate the effect of the sympatholytic drug moxonidine on atherosclerosis. The effects of moxonidine on oxidised low-density lipoprotein (LDL) uptake, inflammatory gene expression and cellular migration were investigated in vitro in cultured vascular smooth muscle cells (VSMCs). The effect of moxonidine on atherosclerosis was measured by examining aortic arch Sudan IV staining and quantifying the intima-to-media ratio of the left common carotid artery in apolipoprotein E-deficient (ApoE
- Authors: Wang, Yutang , Nguyen, Dinh , Anesi, Jack , Alramahi, Ahmed , Witting, Paul , Chai, Zhonglin , Khan, Abdul , Kelly, Jason , Denton, Kate , Golledge, Jonathan
- Date: 2023
- Type: Text , Journal article
- Relation: International Journal of Molecular Sciences Vol. 24, no. 4 (2023), p.
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: This study aimed to investigate the effect of the sympatholytic drug moxonidine on atherosclerosis. The effects of moxonidine on oxidised low-density lipoprotein (LDL) uptake, inflammatory gene expression and cellular migration were investigated in vitro in cultured vascular smooth muscle cells (VSMCs). The effect of moxonidine on atherosclerosis was measured by examining aortic arch Sudan IV staining and quantifying the intima-to-media ratio of the left common carotid artery in apolipoprotein E-deficient (ApoE
A modified MTS proliferation assay for suspended cells to avoid the interference by hydralazine and β-Mercaptoethanol
- Wang, Yutang, Nguyen, Dinh, Anesi, Jack, Kelly, Jason, Ahmady, Fahima, Charchar, Fadi
- Authors: Wang, Yutang , Nguyen, Dinh , Anesi, Jack , Kelly, Jason , Ahmady, Fahima , Charchar, Fadi
- Date: 2021
- Type: Text , Journal article
- Relation: Assay and Drug Development Technologies Vol. 19, no. 3 (2021), p. 184-190. https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay is one of the most commonly used tests of cell proliferation. Hydralazine has been reported to interfere with the performance of the MTS assay when used on adherent cells. This study aimed to investigate whether hydralazine interferes with the performance of the MTS assay on suspended cells. THP-1 (a monocytic leukemia cell line) cells were cultured in the presence or absence of hydralazine (0, 10, 50, 100, and 500 μM) for 2 or 24 h. Cell numbers were analyzed using the MTS, trypan blue exclusion, or microscopic assays. A modified version of the standard MTS assay was established by centrifuging the cells and replacing the test medium with fresh culture medium immediately before the addition of the MTS reagent. Culture of THP-1 cells with hydralazine at concentrations of 50, 100, and 500 μM for 2 h increased absorbance (p < 0.001) in the standard MTS assay, whereas both the trypan blue exclusion assay and microscopy suggested no change in cell numbers. Culture of THP-1 cells with 100 and 500 μm hydralazine for 24 h increased absorbance (p < 0.05) in the standard MTS assay; however, trypan blue exclusion and microscopy suggested a decrease in cell numbers. In a cell-free system, hydralazine (100 and 500 μM) increased absorbance in a time- and concentration-dependent manner. The modified MTS assay produced results consistent with trypan blue exclusion and microscopy using THP-1 cells. In addition, the modified MTS assay produced reliable results when K562 and Jurkat cells were incubated with hydralazine or β-mercaptoethanol (βME). In conclusion, a simple modification of the standard MTS assay overcame the interference of hydralazine and βME when assessing suspended cells. © Copyright 2021, Mary Ann Liebert, Inc., publishers 2021. *Please note that there are multiple authors for this article therefore only the name of the Federation University Australia affiliates “Yutang Wang, Dinh Nguyen, Jack Anesi, Jason Kelly, Fahima Ahmady, Fadi Charchar" is provided in this record**
- Authors: Wang, Yutang , Nguyen, Dinh , Anesi, Jack , Kelly, Jason , Ahmady, Fahima , Charchar, Fadi
- Date: 2021
- Type: Text , Journal article
- Relation: Assay and Drug Development Technologies Vol. 19, no. 3 (2021), p. 184-190. https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay is one of the most commonly used tests of cell proliferation. Hydralazine has been reported to interfere with the performance of the MTS assay when used on adherent cells. This study aimed to investigate whether hydralazine interferes with the performance of the MTS assay on suspended cells. THP-1 (a monocytic leukemia cell line) cells were cultured in the presence or absence of hydralazine (0, 10, 50, 100, and 500 μM) for 2 or 24 h. Cell numbers were analyzed using the MTS, trypan blue exclusion, or microscopic assays. A modified version of the standard MTS assay was established by centrifuging the cells and replacing the test medium with fresh culture medium immediately before the addition of the MTS reagent. Culture of THP-1 cells with hydralazine at concentrations of 50, 100, and 500 μM for 2 h increased absorbance (p < 0.001) in the standard MTS assay, whereas both the trypan blue exclusion assay and microscopy suggested no change in cell numbers. Culture of THP-1 cells with 100 and 500 μm hydralazine for 24 h increased absorbance (p < 0.05) in the standard MTS assay; however, trypan blue exclusion and microscopy suggested a decrease in cell numbers. In a cell-free system, hydralazine (100 and 500 μM) increased absorbance in a time- and concentration-dependent manner. The modified MTS assay produced results consistent with trypan blue exclusion and microscopy using THP-1 cells. In addition, the modified MTS assay produced reliable results when K562 and Jurkat cells were incubated with hydralazine or β-mercaptoethanol (βME). In conclusion, a simple modification of the standard MTS assay overcame the interference of hydralazine and βME when assessing suspended cells. © Copyright 2021, Mary Ann Liebert, Inc., publishers 2021. *Please note that there are multiple authors for this article therefore only the name of the Federation University Australia affiliates “Yutang Wang, Dinh Nguyen, Jack Anesi, Jason Kelly, Fahima Ahmady, Fadi Charchar" is provided in this record**
An improved 3-(4,5-dmethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl )-2H-tetrazolium proliferation assay to overcome the interference of hydralazine
- Wang, Yutang, Nguyen, Dinh, Yang, Guang, Anesi, Jack, Chai, Zhonglin, Charchar, Fadi, Golledge, Jonathan
- Authors: Wang, Yutang , Nguyen, Dinh , Yang, Guang , Anesi, Jack , Chai, Zhonglin , Charchar, Fadi , Golledge, Jonathan
- Date: 2020
- Type: Text , Journal article
- Relation: Assay and Drug Development Technologies Vol. 18, no. 8 (Dec 2020), p. 379-384
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: The MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay is one of the most commonly used assays to assess cell proliferation and cytotoxicity, but is subject to interference by testing compounds. Hydralazine, an antihypertensive drug, is commonly investigated in multiple fields such as heart failure, cancer, and blood pressure research. This study reported interference of the MTS assay by hydralazine and a simple modification overcoming this interference. Vascular smooth muscle cells were cultured in the presence or absence of hydralazine (0, 10, 50,100, and 500 mu M) for 2 or 24 h. Cell numbers were analyzed using MTS, trypan blue exclusion, or microscopic assays. A modified version of the standard MTS assay was established, in which an additional step was added replacing the test medium, containing hydralazine, with fresh culture medium immediately before the addition of the MTS reagent. Culture with hydralazine at concentrations of 50, 100, and 500 mu M for 2 h increased absorbance (p< 0.05) in the standard MTS assay, whereas microscopy suggested no change in cell numbers. Culture with 500 mu m hydralazine for 24 h increased absorbance (p< 0.05) in the standard MTS assay, however, trypan blue exclusion and microscopy suggested a decrease in cell numbers. In a cell-free system, hydralazine (>= 10 mu M) increased absorbance in a concentration-dependent manner. The modified MTS assay produced results consistent with trypan blue exclusion and microscopy. In conclusion, a simple modification of the standard MTS assay overcame the interference of hydralazine and may be useful to avoid interference from other tested compounds.
- Authors: Wang, Yutang , Nguyen, Dinh , Yang, Guang , Anesi, Jack , Chai, Zhonglin , Charchar, Fadi , Golledge, Jonathan
- Date: 2020
- Type: Text , Journal article
- Relation: Assay and Drug Development Technologies Vol. 18, no. 8 (Dec 2020), p. 379-384
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: The MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay is one of the most commonly used assays to assess cell proliferation and cytotoxicity, but is subject to interference by testing compounds. Hydralazine, an antihypertensive drug, is commonly investigated in multiple fields such as heart failure, cancer, and blood pressure research. This study reported interference of the MTS assay by hydralazine and a simple modification overcoming this interference. Vascular smooth muscle cells were cultured in the presence or absence of hydralazine (0, 10, 50,100, and 500 mu M) for 2 or 24 h. Cell numbers were analyzed using MTS, trypan blue exclusion, or microscopic assays. A modified version of the standard MTS assay was established, in which an additional step was added replacing the test medium, containing hydralazine, with fresh culture medium immediately before the addition of the MTS reagent. Culture with hydralazine at concentrations of 50, 100, and 500 mu M for 2 h increased absorbance (p< 0.05) in the standard MTS assay, whereas microscopy suggested no change in cell numbers. Culture with 500 mu m hydralazine for 24 h increased absorbance (p< 0.05) in the standard MTS assay, however, trypan blue exclusion and microscopy suggested a decrease in cell numbers. In a cell-free system, hydralazine (>= 10 mu M) increased absorbance in a concentration-dependent manner. The modified MTS assay produced results consistent with trypan blue exclusion and microscopy. In conclusion, a simple modification of the standard MTS assay overcame the interference of hydralazine and may be useful to avoid interference from other tested compounds.
Sympathetic nervous system and atherosclerosis
- Wang, Yutang, Anesi, Jack, Maier, Michelle, Myers, Mark, Oqueli, Ernesto, Sobey, Christopher, Drummond, Grant, Denton, Kate
- Authors: Wang, Yutang , Anesi, Jack , Maier, Michelle , Myers, Mark , Oqueli, Ernesto , Sobey, Christopher , Drummond, Grant , Denton, Kate
- Date: 2023
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 24, no. 17 (2023), p.
- Full Text:
- Reviewed:
- Description: Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (
- Authors: Wang, Yutang , Anesi, Jack , Maier, Michelle , Myers, Mark , Oqueli, Ernesto , Sobey, Christopher , Drummond, Grant , Denton, Kate
- Date: 2023
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 24, no. 17 (2023), p.
- Full Text:
- Reviewed:
- Description: Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (
Effect of hydralazine on angiotensin II-induced abdominal aortic aneurysm in apolipoprotein e-deficient mice
- Wang, Yutang, Sargisson, Owen, Nguyen, Dinh, Parker, Ketura, Pyke, Stephan, Alramahi, Ahmed, Thihlum, Liam, Fang, Yan, Wallace, Morgan, Berzins, Stuart, Oqueli, Ernesto, Magliano, Dianna, Golledge, Jonathan
- Authors: Wang, Yutang , Sargisson, Owen , Nguyen, Dinh , Parker, Ketura , Pyke, Stephan , Alramahi, Ahmed , Thihlum, Liam , Fang, Yan , Wallace, Morgan , Berzins, Stuart , Oqueli, Ernesto , Magliano, Dianna , Golledge, Jonathan
- Date: 2023
- Type: Text , Journal article
- Relation: International Journal of Molecular Sciences Vol. 24, no. 21 (2023), p.
- Full Text:
- Reviewed:
- Description: The rupture of an abdominal aortic aneurysm (AAA) causes about 200,000 deaths worldwide each year. However, there are currently no effective drug therapies to prevent AAA formation or, when present, to decrease progression and rupture, highlighting an urgent need for more research in this field. Increased vascular inflammation and enhanced apoptosis of vascular smooth muscle cells (VSMCs) are implicated in AAA formation. Here, we investigated whether hydralazine, which has anti-inflammatory and anti-apoptotic properties, inhibited AAA formation and pathological hallmarks. In cultured VSMCs, hydralazine (100
- Authors: Wang, Yutang , Sargisson, Owen , Nguyen, Dinh , Parker, Ketura , Pyke, Stephan , Alramahi, Ahmed , Thihlum, Liam , Fang, Yan , Wallace, Morgan , Berzins, Stuart , Oqueli, Ernesto , Magliano, Dianna , Golledge, Jonathan
- Date: 2023
- Type: Text , Journal article
- Relation: International Journal of Molecular Sciences Vol. 24, no. 21 (2023), p.
- Full Text:
- Reviewed:
- Description: The rupture of an abdominal aortic aneurysm (AAA) causes about 200,000 deaths worldwide each year. However, there are currently no effective drug therapies to prevent AAA formation or, when present, to decrease progression and rupture, highlighting an urgent need for more research in this field. Increased vascular inflammation and enhanced apoptosis of vascular smooth muscle cells (VSMCs) are implicated in AAA formation. Here, we investigated whether hydralazine, which has anti-inflammatory and anti-apoptotic properties, inhibited AAA formation and pathological hallmarks. In cultured VSMCs, hydralazine (100
Adjustment for body mass index changes inverse associations of HDL-cholesterol with blood pressure and hypertension to positive associations
- Yang, Guang, Qian, Tingting, Sun, Hui, Xu, Qun, Hou, Xujuan, Hu, Wenqi, Zhang, Guang, Drummond, Grant, Sobey, Christopher, Witting, Paul, Denton, Kate, Charchar, Fadi, Golledge, Jonathan, Wang, Yutang
- Authors: Yang, Guang , Qian, Tingting , Sun, Hui , Xu, Qun , Hou, Xujuan , Hu, Wenqi , Zhang, Guang , Drummond, Grant , Sobey, Christopher , Witting, Paul , Denton, Kate , Charchar, Fadi , Golledge, Jonathan , Wang, Yutang
- Date: 2022
- Type: Text , Journal article
- Relation: Journal of Human Hypertension Vol. 36, no. 6 (2022), p. 570-579
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: The associations between high-density lipoprotein cholesterol (HDL-C) and blood pressure (BP) or hypertension are inconsistent in previous studies. This study aimed to assess these associations in a large cohort of Chinese adults and across different age groups. This cross-sectional association study included 22,081 Chinese adults. Associations of HDL-C with BP and hypertension were analyzed using linear or logistic regression, with or without adjustment for confounding factors. HDL-C was inversely associated with BP and hypertension. These associations were still apparent after adjustment for age, sex, fasting plasma glucose, and low-density lipoprotein cholesterol. Sub-analyses revealed: (1) in the whole cohort and females alone, HDL-C was inversely associated with BP and hypertension in young and middle-aged but not older participants; (2) in males alone, HDL-C was not associated with systolic BP or hypertension. However, HDL-C was either inversely, or not, or positively associated with BP in young, middle-aged, and older males, respectively. After further adjustment for body mass index (BMI), the negative associations of HDL-C with BP and hypertension in the whole cohort became positive ones, and the positive associations only presented in males. These findings suggest that further adjustment for BMI changes inverse associations of HDL-cholesterol with BP and hypertension to positive associations in a cohort of Chinese adults. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
- Authors: Yang, Guang , Qian, Tingting , Sun, Hui , Xu, Qun , Hou, Xujuan , Hu, Wenqi , Zhang, Guang , Drummond, Grant , Sobey, Christopher , Witting, Paul , Denton, Kate , Charchar, Fadi , Golledge, Jonathan , Wang, Yutang
- Date: 2022
- Type: Text , Journal article
- Relation: Journal of Human Hypertension Vol. 36, no. 6 (2022), p. 570-579
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: The associations between high-density lipoprotein cholesterol (HDL-C) and blood pressure (BP) or hypertension are inconsistent in previous studies. This study aimed to assess these associations in a large cohort of Chinese adults and across different age groups. This cross-sectional association study included 22,081 Chinese adults. Associations of HDL-C with BP and hypertension were analyzed using linear or logistic regression, with or without adjustment for confounding factors. HDL-C was inversely associated with BP and hypertension. These associations were still apparent after adjustment for age, sex, fasting plasma glucose, and low-density lipoprotein cholesterol. Sub-analyses revealed: (1) in the whole cohort and females alone, HDL-C was inversely associated with BP and hypertension in young and middle-aged but not older participants; (2) in males alone, HDL-C was not associated with systolic BP or hypertension. However, HDL-C was either inversely, or not, or positively associated with BP in young, middle-aged, and older males, respectively. After further adjustment for body mass index (BMI), the negative associations of HDL-C with BP and hypertension in the whole cohort became positive ones, and the positive associations only presented in males. These findings suggest that further adjustment for BMI changes inverse associations of HDL-cholesterol with BP and hypertension to positive associations in a cohort of Chinese adults. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
Prior cancer diagnosis and mortality profile in US adults
- Wang, Yutang, Fang, Yan, Sobey, Christopher, Drummond, Grant
- Authors: Wang, Yutang , Fang, Yan , Sobey, Christopher , Drummond, Grant
- Date: 2023
- Type: Text , Journal article
- Relation: American Journal of the Medical Sciences Vol. 365, no. 2 (2023), p. 176-183
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Background: Mortality profiles with multivariate adjustment in patients with a prior cancer diagnosis are scarce. This study aimed to investigate multivariate-adjusted mortality profile in US adults with a prior cancer diagnosis. Methods: This cohort study included 58,109 US adults (5,016 with a prior cancer diagnosis) who attended the National Health and Nutrition Examination Survey. Mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and confidence intervals (CIs) of prior cancer diagnosis for mortality. Results: This cohort was followed up for 646,033 person-years with a mean follow-up of 11.1 years. Compared with those without cancer, participants with a prior cancer diagnosis had increased crude cumulative mortality rates in each leading cause. Prior cancer diagnosis was associated with a higher multivariate-adjusted risk of mortality from all causes (HR, 1.29; 95% CI, 1.22-1.35), cancer (HR, 2.32; 95% CI, 2.10-2.56), and accidents (HR, 1.90; 95% CI, 1.34-2.68). Prior cancer diagnosis-associated increase in accident mortality appeared only in males and was significant only in non-Hispanic black participants. Prior cancer diagnosis-associated increase in cancer mortality appeared high in non-Hispanic black participants. Conclusions: This study found that patients with a prior cancer diagnosis had higher multivariate-adjusted accident mortality risks, suggesting that oncologists may need to evaluate accident risks in cancer patients and provide preventive interventions in particular for male and non-Hispanic black patients. Increased cancer mortality risk associated with prior cancer diagnosis in non-Hispanic black participants may also need clinical attention. © 2022 Southern Society for Clinical Investigation
- Authors: Wang, Yutang , Fang, Yan , Sobey, Christopher , Drummond, Grant
- Date: 2023
- Type: Text , Journal article
- Relation: American Journal of the Medical Sciences Vol. 365, no. 2 (2023), p. 176-183
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Background: Mortality profiles with multivariate adjustment in patients with a prior cancer diagnosis are scarce. This study aimed to investigate multivariate-adjusted mortality profile in US adults with a prior cancer diagnosis. Methods: This cohort study included 58,109 US adults (5,016 with a prior cancer diagnosis) who attended the National Health and Nutrition Examination Survey. Mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and confidence intervals (CIs) of prior cancer diagnosis for mortality. Results: This cohort was followed up for 646,033 person-years with a mean follow-up of 11.1 years. Compared with those without cancer, participants with a prior cancer diagnosis had increased crude cumulative mortality rates in each leading cause. Prior cancer diagnosis was associated with a higher multivariate-adjusted risk of mortality from all causes (HR, 1.29; 95% CI, 1.22-1.35), cancer (HR, 2.32; 95% CI, 2.10-2.56), and accidents (HR, 1.90; 95% CI, 1.34-2.68). Prior cancer diagnosis-associated increase in accident mortality appeared only in males and was significant only in non-Hispanic black participants. Prior cancer diagnosis-associated increase in cancer mortality appeared high in non-Hispanic black participants. Conclusions: This study found that patients with a prior cancer diagnosis had higher multivariate-adjusted accident mortality risks, suggesting that oncologists may need to evaluate accident risks in cancer patients and provide preventive interventions in particular for male and non-Hispanic black patients. Increased cancer mortality risk associated with prior cancer diagnosis in non-Hispanic black participants may also need clinical attention. © 2022 Southern Society for Clinical Investigation
Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation
- Stanley, Christopher, Maghzal, Ghassan, Ayer, Anita, Talib, Jihan, Giltrap, Andrew, Shengule, Sudhir, Wolhuter, Kathryn, Wang, Yutang, Chadha, Preet, Suarna, Cacang, Prysyazhna, Oleksandra, Scotcher, Jenna, Dunn, Louise, Prado, Fernanda, Nguyen, Nghi, Odiba, Jephthah, Baell, Johathan, Stasch, Johannes-Peter, Yamamoto, Yorihiro, Di Mascio, Paolo, Eaton, Philip, Payne, Richard, Stocker, Roland
- Authors: Stanley, Christopher , Maghzal, Ghassan , Ayer, Anita , Talib, Jihan , Giltrap, Andrew , Shengule, Sudhir , Wolhuter, Kathryn , Wang, Yutang , Chadha, Preet , Suarna, Cacang , Prysyazhna, Oleksandra , Scotcher, Jenna , Dunn, Louise , Prado, Fernanda , Nguyen, Nghi , Odiba, Jephthah , Baell, Johathan , Stasch, Johannes-Peter , Yamamoto, Yorihiro , Di Mascio, Paolo , Eaton, Philip , Payne, Richard , Stocker, Roland
- Date: 2019
- Type: Text , Journal article , Letter
- Relation: Nature Vol. 566, no. 7745 (2019), p. 548-552
- Full Text:
- Reviewed:
- Description: Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(2) oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine(4), whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1(5). Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure(6). However, whether indoleamine 2,3-dioxygenase 1 forms O-1(2) and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(2) and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1 alpha. Our findings demonstrate a pathophysiological role for O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.
- Authors: Stanley, Christopher , Maghzal, Ghassan , Ayer, Anita , Talib, Jihan , Giltrap, Andrew , Shengule, Sudhir , Wolhuter, Kathryn , Wang, Yutang , Chadha, Preet , Suarna, Cacang , Prysyazhna, Oleksandra , Scotcher, Jenna , Dunn, Louise , Prado, Fernanda , Nguyen, Nghi , Odiba, Jephthah , Baell, Johathan , Stasch, Johannes-Peter , Yamamoto, Yorihiro , Di Mascio, Paolo , Eaton, Philip , Payne, Richard , Stocker, Roland
- Date: 2019
- Type: Text , Journal article , Letter
- Relation: Nature Vol. 566, no. 7745 (2019), p. 548-552
- Full Text:
- Reviewed:
- Description: Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(2) oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine(4), whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1(5). Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure(6). However, whether indoleamine 2,3-dioxygenase 1 forms O-1(2) and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(2) and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1 alpha. Our findings demonstrate a pathophysiological role for O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.
Fasting triglycerides are positively associated with cardiovascular mortality risk in people with diabetes
- Wang, Yutang, Fang, Yan, Magliano, Dianna, Charchar, Fadi, Sobey, Christopher, Drummond, Grant, Golledge, Jonathan
- Authors: Wang, Yutang , Fang, Yan , Magliano, Dianna , Charchar, Fadi , Sobey, Christopher , Drummond, Grant , Golledge, Jonathan
- Date: 2023
- Type: Text , Journal article
- Relation: Cardiovascular Research Vol. 119, no. 3 (2023), p. 826-834
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Aims We investigated the association of fasting triglycerides with cardiovascular disease (CVD) mortality. Methods and results This cohort study included US adults from the National Health and Nutrition Examination Surveys from 1988 to 2014. CVD mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of triglycerides for CVD mortality. The cohort included 26 570 adult participants, among which 3978 had diabetes. People with higher triglycerides had a higher prevalence of diabetes at baseline. The cohort was followed up for a mean of 12.0 years with 1492 CVD deaths recorded. A 1-natural-log-unit higher triglyceride was associated with a 30% higher multivariate-adjusted risk of CVD mortality in participants with diabetes (HR, 1.30; 95% CI, 1.08–1.56) but not in those without diabetes (HR, 0.95; 95% CI, 0.83–1.07). In participants with diabetes, people with high triglycerides (200–499 mg/dL) had a 44% (HR, 1.44; 95% CI, 1.12–1.85) higher multivariate-adjusted risk of CVD mortality compared with those with normal triglycerides (<150 mg/dL). The findings remained significant when diabetes was defined by fasting glucose levels alone, or after further adjustment for the use of lipid-lowering medications, or after the exclusion of those who took lipid-lowering medications. Conclusion This study demonstrates that fasting triglycerides of
- Authors: Wang, Yutang , Fang, Yan , Magliano, Dianna , Charchar, Fadi , Sobey, Christopher , Drummond, Grant , Golledge, Jonathan
- Date: 2023
- Type: Text , Journal article
- Relation: Cardiovascular Research Vol. 119, no. 3 (2023), p. 826-834
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Aims We investigated the association of fasting triglycerides with cardiovascular disease (CVD) mortality. Methods and results This cohort study included US adults from the National Health and Nutrition Examination Surveys from 1988 to 2014. CVD mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of triglycerides for CVD mortality. The cohort included 26 570 adult participants, among which 3978 had diabetes. People with higher triglycerides had a higher prevalence of diabetes at baseline. The cohort was followed up for a mean of 12.0 years with 1492 CVD deaths recorded. A 1-natural-log-unit higher triglyceride was associated with a 30% higher multivariate-adjusted risk of CVD mortality in participants with diabetes (HR, 1.30; 95% CI, 1.08–1.56) but not in those without diabetes (HR, 0.95; 95% CI, 0.83–1.07). In participants with diabetes, people with high triglycerides (200–499 mg/dL) had a 44% (HR, 1.44; 95% CI, 1.12–1.85) higher multivariate-adjusted risk of CVD mortality compared with those with normal triglycerides (<150 mg/dL). The findings remained significant when diabetes was defined by fasting glucose levels alone, or after further adjustment for the use of lipid-lowering medications, or after the exclusion of those who took lipid-lowering medications. Conclusion This study demonstrates that fasting triglycerides of
Mouse models for abdominal aortic aneurysm
- Golledge, Jonathan, Krishna, Smriti, Wang, Yutang
- Authors: Golledge, Jonathan , Krishna, Smriti , Wang, Yutang
- Date: 2022
- Type: Text , Journal article , Review
- Relation: British Journal of Pharmacology Vol. 179, no. 5 (2022), p. 792-810
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- Description: Abdominal aortic aneurysm (AAA) rupture is estimated to cause 200,000 deaths each year. Currently, the only treatment for AAA is surgical repair; however, this is only indicated for large asymptomatic, symptomatic or ruptured aneurysms, is not always durable, and is associated with a risk of serious perioperative complications. As a result, patients with small asymptomatic aneurysms or who are otherwise unfit for surgery are treated conservatively, but up to 70% of small aneurysms continue to grow, increasing the risk of rupture. There is thus an urgent need to develop drug therapies effective at slowing AAA growth. This review describes the commonly used mouse models for AAA. Recent research in these models highlights key roles for pathways involved in inflammation and cell turnover in AAA pathogenesis. There is also evidence for long non-coding RNAs and thrombosis in aneurysm pathology. Further well-designed research in clinically relevant models is expected to be translated into effective AAA drugs. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc. © 2020 The British Pharmacological Society
- Authors: Golledge, Jonathan , Krishna, Smriti , Wang, Yutang
- Date: 2022
- Type: Text , Journal article , Review
- Relation: British Journal of Pharmacology Vol. 179, no. 5 (2022), p. 792-810
- Full Text:
- Reviewed:
- Description: Abdominal aortic aneurysm (AAA) rupture is estimated to cause 200,000 deaths each year. Currently, the only treatment for AAA is surgical repair; however, this is only indicated for large asymptomatic, symptomatic or ruptured aneurysms, is not always durable, and is associated with a risk of serious perioperative complications. As a result, patients with small asymptomatic aneurysms or who are otherwise unfit for surgery are treated conservatively, but up to 70% of small aneurysms continue to grow, increasing the risk of rupture. There is thus an urgent need to develop drug therapies effective at slowing AAA growth. This review describes the commonly used mouse models for AAA. Recent research in these models highlights key roles for pathways involved in inflammation and cell turnover in AAA pathogenesis. There is also evidence for long non-coding RNAs and thrombosis in aneurysm pathology. Further well-designed research in clinically relevant models is expected to be translated into effective AAA drugs. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc. © 2020 The British Pharmacological Society
Late non-fasting plasma glucose predicts cardiovascular mortality independent of hemoglobin A1c
- Authors: Wang, Yutang , Fang, Yan
- Date: 2022
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 12, no. 1 (2022), p.
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- Description: It is unknown whether non-fasting plasma glucose (PG) is associated with cardiovascular disease (CVD) mortality. This study aimed to investigate this association in US adults. This study included adults from the National Health and Nutrition Examination Surveys from 1988 to 2014. Mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of PG for CVD mortality. Among 34,907 participants, 1956, 5564, and 27,387 had PG from participants in early non-fasting, late non-fasting, and fasting states, respectively (defined as a period since last calorie intake of 0–2.9, 3.0–7.9, or
- Authors: Wang, Yutang , Fang, Yan
- Date: 2022
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 12, no. 1 (2022), p.
- Full Text:
- Reviewed:
- Description: It is unknown whether non-fasting plasma glucose (PG) is associated with cardiovascular disease (CVD) mortality. This study aimed to investigate this association in US adults. This study included adults from the National Health and Nutrition Examination Surveys from 1988 to 2014. Mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of PG for CVD mortality. Among 34,907 participants, 1956, 5564, and 27,387 had PG from participants in early non-fasting, late non-fasting, and fasting states, respectively (defined as a period since last calorie intake of 0–2.9, 3.0–7.9, or
Hypouricemia is a risk factor for diabetes in Chinese adults
- Wang, Yutang, Shao, Yanan, Qian, Tingting, Sun, Hui, Xu, Qun, Hou, Xujuan, Hu, Wenqi, Zhang, Guang, Song, David, Fang, Yan, Magliano, Dianna, Witting, Paul, Golledge, Jonathan, Yang, Guang
- Authors: Wang, Yutang , Shao, Yanan , Qian, Tingting , Sun, Hui , Xu, Qun , Hou, Xujuan , Hu, Wenqi , Zhang, Guang , Song, David , Fang, Yan , Magliano, Dianna , Witting, Paul , Golledge, Jonathan , Yang, Guang
- Date: 2022
- Type: Text , Journal article
- Relation: Obesity Medicine Vol. 31, no. (2022), p.
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
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- Description: Aims: It is unknown whether low serum uric acid (hypouricemia) is associated with diabetes diagnosis. This study aimed to investigate this association in Chinese adults. Methods: This cross-sectional study included 22,546 Chinese adults. The reference interval for serum uric acid was determined in a sub-group of healthy individuals. The association between hypouricemia and diabetes was analyzed using binary logistic regression. Results: The serum uric acid reference intervals were 3.78–8.31 mg/dL for males and 2.76–6.24 mg/dL for females. Hypouricemia was defined as serum uric acid concentration <3.78 mg/dL for males and <2.76 mg/dL for females. Hypouricemia was associated with an increased likelihood of diabetes diagnosis in both unadjusted (odds ratio [OR], 2.23; 95% confidence interval [CI], 1.78–2.79) and risk factor adjusted (OR, 2.67; 95% CI, 2.08–3.43) analyses. In a sub-group analysis, hypouricemia was significantly independently associated with an increased likelihood of diabetes diagnosis in males but not females. Conclusion: This study suggests that hypouricemia is independently associated with an increased risk of diabetes diagnosis. The findings should be validated in prospective cohort studies. © 2022 Elsevier Ltd
- Authors: Wang, Yutang , Shao, Yanan , Qian, Tingting , Sun, Hui , Xu, Qun , Hou, Xujuan , Hu, Wenqi , Zhang, Guang , Song, David , Fang, Yan , Magliano, Dianna , Witting, Paul , Golledge, Jonathan , Yang, Guang
- Date: 2022
- Type: Text , Journal article
- Relation: Obesity Medicine Vol. 31, no. (2022), p.
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Aims: It is unknown whether low serum uric acid (hypouricemia) is associated with diabetes diagnosis. This study aimed to investigate this association in Chinese adults. Methods: This cross-sectional study included 22,546 Chinese adults. The reference interval for serum uric acid was determined in a sub-group of healthy individuals. The association between hypouricemia and diabetes was analyzed using binary logistic regression. Results: The serum uric acid reference intervals were 3.78–8.31 mg/dL for males and 2.76–6.24 mg/dL for females. Hypouricemia was defined as serum uric acid concentration <3.78 mg/dL for males and <2.76 mg/dL for females. Hypouricemia was associated with an increased likelihood of diabetes diagnosis in both unadjusted (odds ratio [OR], 2.23; 95% confidence interval [CI], 1.78–2.79) and risk factor adjusted (OR, 2.67; 95% CI, 2.08–3.43) analyses. In a sub-group analysis, hypouricemia was significantly independently associated with an increased likelihood of diabetes diagnosis in males but not females. Conclusion: This study suggests that hypouricemia is independently associated with an increased risk of diabetes diagnosis. The findings should be validated in prospective cohort studies. © 2022 Elsevier Ltd
Renal denervation promotes atherosclerosis in hypertensive apolipoprotein E-Deficient mice infused with angiotensin II
- Wang, Yutang, Dinh, Tam, Nield, Alex, Krishna, Smriti, Denton, Kate, Golledge, Jonathan
- Authors: Wang, Yutang , Dinh, Tam , Nield, Alex , Krishna, Smriti , Denton, Kate , Golledge, Jonathan
- Date: 2017
- Type: Text , Journal article
- Relation: Frontiers in Physiology Vol. 8, no. (2017), p. 1-9
- Relation: http://purl.org/au-research/grants/nhmrc/1062671
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- Description: Objective: To determine the effect of renal denervation (RDN) on the severity of atherosclerosis and aortic aneurysm in hypertensive mice. Methods: Hypertension, atherosclerosis and aortic aneurysm were induced by subcutaneous infusion of angiotensin II (1 μg/kg/min) for 28 days in apolipoprotein E-deficient mice. RDN was conducted using combined surgical and local chemical denervation. The norepinephrine concentration in the kidney was measured by high-performance liquid chromatography. Blood pressure was measured by the tail-cuff method. Atherosclerosis was assessed by Sudan IV staining of the aortic arch. The aortic diameter was measured by the morphometric method. The mRNA expression of genes associated with atherosclerosis and aortic aneurysm were analyzed by quantitative PCR. Results: RDN decreased the median norepinephrine content in the kidney by 93.4% (n = 5-7, P = 0.003) 5 days after the procedure, indicating that the RDN procedure was successful. RDN decreased systolic blood pressure in apolipoprotein E-deficient mice. Mice that had RDN had more severe aortic arch atherosclerosis (median percentage of Sudan IV positive area: 13.2% in control mice, n = 12, and 25.4% in mice having RDN, n = 12, P = 0.028). The severity of the atherosclerosis was negatively correlated with the renal norepinephrine content (spearman r = -0.6557, P = 0.005). RDN did not affect the size of aortic aneurysms formed or the incidence of aortic rupture in mice receiving angiotensin II. RDN significantly increased the aortic mRNA expression of matrix metalloproteinase-2 (MMP-2). Conclusion: RDN promoted atherosclerosis in apolipoprotein E-deficient mice infused with angiotensin II associated with upregulation of MMP-2. The higher MMP-2 expression could be the results of the greater amount of atheroma in the RDN mice. The findings suggest further research is needed to assess potentially deleterious effects of RDN in patients. © 2017 Wang, Dinh, Nield, Krishna, Denton and Golledge.
- Authors: Wang, Yutang , Dinh, Tam , Nield, Alex , Krishna, Smriti , Denton, Kate , Golledge, Jonathan
- Date: 2017
- Type: Text , Journal article
- Relation: Frontiers in Physiology Vol. 8, no. (2017), p. 1-9
- Relation: http://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Objective: To determine the effect of renal denervation (RDN) on the severity of atherosclerosis and aortic aneurysm in hypertensive mice. Methods: Hypertension, atherosclerosis and aortic aneurysm were induced by subcutaneous infusion of angiotensin II (1 μg/kg/min) for 28 days in apolipoprotein E-deficient mice. RDN was conducted using combined surgical and local chemical denervation. The norepinephrine concentration in the kidney was measured by high-performance liquid chromatography. Blood pressure was measured by the tail-cuff method. Atherosclerosis was assessed by Sudan IV staining of the aortic arch. The aortic diameter was measured by the morphometric method. The mRNA expression of genes associated with atherosclerosis and aortic aneurysm were analyzed by quantitative PCR. Results: RDN decreased the median norepinephrine content in the kidney by 93.4% (n = 5-7, P = 0.003) 5 days after the procedure, indicating that the RDN procedure was successful. RDN decreased systolic blood pressure in apolipoprotein E-deficient mice. Mice that had RDN had more severe aortic arch atherosclerosis (median percentage of Sudan IV positive area: 13.2% in control mice, n = 12, and 25.4% in mice having RDN, n = 12, P = 0.028). The severity of the atherosclerosis was negatively correlated with the renal norepinephrine content (spearman r = -0.6557, P = 0.005). RDN did not affect the size of aortic aneurysms formed or the incidence of aortic rupture in mice receiving angiotensin II. RDN significantly increased the aortic mRNA expression of matrix metalloproteinase-2 (MMP-2). Conclusion: RDN promoted atherosclerosis in apolipoprotein E-deficient mice infused with angiotensin II associated with upregulation of MMP-2. The higher MMP-2 expression could be the results of the greater amount of atheroma in the RDN mice. The findings suggest further research is needed to assess potentially deleterious effects of RDN in patients. © 2017 Wang, Dinh, Nield, Krishna, Denton and Golledge.
Fasting status modifies the association between triglyceride and all-cause mortality : a cohort study
- Authors: Fang, Yan , Wang, Yutang
- Date: 2022
- Type: Text , Journal article
- Relation: Health Science Reports Vol. 5, no. 3 (2022), p.
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- Description: Background and Aims: Both fasting and non-fasting levels of triglyceride have been shown positively associated with all-cause mortality. It is unknown whether fasting status modifies this association. This study aimed to address this question. Methods: This study included 34,512 US adults (27,036 fasting and 7476 nonfasting participants). All-cause mortality was ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios of triglyceride for mortality. Results: This cohort was followed up for a mean of 13.0 years. During the follow-up, 8491 all-cause deaths were recorded. A 1-natural-log-unit increase in triglyceride was associated with an 8% higher multivariate-adjusted risk of all-cause mortality. Interaction analyses showed that fasting status interacted with triglyceride in predicting all-cause mortality. Sub-analyses showed that a 1-natural-log-unit increase in triglyceride was associated with a 17% higher multivariate-adjusted risk of all-cause mortality in the nonfasting subcohort; however, there lacked such an association in the fasting sub-cohort. Similarly, high (200–499 mg/dL) and very high levels of triglyceride (
- Authors: Fang, Yan , Wang, Yutang
- Date: 2022
- Type: Text , Journal article
- Relation: Health Science Reports Vol. 5, no. 3 (2022), p.
- Full Text:
- Reviewed:
- Description: Background and Aims: Both fasting and non-fasting levels of triglyceride have been shown positively associated with all-cause mortality. It is unknown whether fasting status modifies this association. This study aimed to address this question. Methods: This study included 34,512 US adults (27,036 fasting and 7476 nonfasting participants). All-cause mortality was ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios of triglyceride for mortality. Results: This cohort was followed up for a mean of 13.0 years. During the follow-up, 8491 all-cause deaths were recorded. A 1-natural-log-unit increase in triglyceride was associated with an 8% higher multivariate-adjusted risk of all-cause mortality. Interaction analyses showed that fasting status interacted with triglyceride in predicting all-cause mortality. Sub-analyses showed that a 1-natural-log-unit increase in triglyceride was associated with a 17% higher multivariate-adjusted risk of all-cause mortality in the nonfasting subcohort; however, there lacked such an association in the fasting sub-cohort. Similarly, high (200–499 mg/dL) and very high levels of triglyceride (
Wnt signaling pathway inhibitor Sclerostin inhibits angiotensin II-induced aortic aneurysm and atherosclerosis
- Krishna, Smriti, Seto, Sai-Wang, Jose, Roby, Li, Jiaze, Morton, Susan, Biros, Erik, Wang, Yutang, Nsengiyumva, Vianne, Lindeman, Jan, Loots, Gabriela, Rush, Catherine, Craig, Jeffrey, Golledge, Jonathan
- Authors: Krishna, Smriti , Seto, Sai-Wang , Jose, Roby , Li, Jiaze , Morton, Susan , Biros, Erik , Wang, Yutang , Nsengiyumva, Vianne , Lindeman, Jan , Loots, Gabriela , Rush, Catherine , Craig, Jeffrey , Golledge, Jonathan
- Date: 2017
- Type: Text , Journal article
- Relation: Arteriosclerosis Thrombosis and Vascular Biology Vol. 37, no. 3 (2017), p. 553-566
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- Description: Objective-Sclerostin (SOST) has been identified as an important regulator of bone formation; however, it has not been previously implicated in arterial disease. The aim of this study was to assess the role of SOST in aortic aneurysm (AA) and atherosclerosis using human samples, a mouse model, and in vitro investigations. Approach and Results-SOST protein was downregulated in human and mouse AA samples compared with controls. Transgenic introduction of human SOST in apolipoprotein E-deficient (ApoE(-/-)) mice (SOSTTg. ApoE(-/-)) and administration of recombinant mouse Sost inhibited angiotensin II-induced AA and atherosclerosis. Serum concentrations of several proinflammatory cytokines were significantly reduced in SOSTTg. ApoE(-/-) mice. Compared with controls, the aortas of mice receiving recombinant mouse Sost and SOSTTg. ApoE(-/-) mice showed reduced matrix degradation, reduced elastin breaks, and preserved collagen. Decreased inflammatory cell infiltration and a reduction in the expression of wingless-type mouse mammary virus integration site/beta-catenin responsive genes, including matrix metalloproteinase-9, osteoprotegerin, and osteopontin, were observed in the aortas of SOSTTg. ApoE(-/-) mice. SOST expression was downregulated and the winglesstype mouse mammary virus integration site/beta-catenin pathway was activated in human AA samples. The cytosinephosphate- guanine islands in the SOST gene promoter showed significantly higher methylation in human AA samples compared with controls. Incubation of vascular smooth muscle cells with the demethylating agent 5-azacytidine resulted in upregulation of SOST, suggesting that SOST is epigenetically regulated. Conclusions-This study identifies that SOST is expressed in the aorta and downregulated in human AA possibly because of epigenetic silencing. Upregulating SOST inhibits AA and atherosclerosis development, with potential important implications for treating these vascular diseases.
- Authors: Krishna, Smriti , Seto, Sai-Wang , Jose, Roby , Li, Jiaze , Morton, Susan , Biros, Erik , Wang, Yutang , Nsengiyumva, Vianne , Lindeman, Jan , Loots, Gabriela , Rush, Catherine , Craig, Jeffrey , Golledge, Jonathan
- Date: 2017
- Type: Text , Journal article
- Relation: Arteriosclerosis Thrombosis and Vascular Biology Vol. 37, no. 3 (2017), p. 553-566
- Full Text:
- Reviewed:
- Description: Objective-Sclerostin (SOST) has been identified as an important regulator of bone formation; however, it has not been previously implicated in arterial disease. The aim of this study was to assess the role of SOST in aortic aneurysm (AA) and atherosclerosis using human samples, a mouse model, and in vitro investigations. Approach and Results-SOST protein was downregulated in human and mouse AA samples compared with controls. Transgenic introduction of human SOST in apolipoprotein E-deficient (ApoE(-/-)) mice (SOSTTg. ApoE(-/-)) and administration of recombinant mouse Sost inhibited angiotensin II-induced AA and atherosclerosis. Serum concentrations of several proinflammatory cytokines were significantly reduced in SOSTTg. ApoE(-/-) mice. Compared with controls, the aortas of mice receiving recombinant mouse Sost and SOSTTg. ApoE(-/-) mice showed reduced matrix degradation, reduced elastin breaks, and preserved collagen. Decreased inflammatory cell infiltration and a reduction in the expression of wingless-type mouse mammary virus integration site/beta-catenin responsive genes, including matrix metalloproteinase-9, osteoprotegerin, and osteopontin, were observed in the aortas of SOSTTg. ApoE(-/-) mice. SOST expression was downregulated and the winglesstype mouse mammary virus integration site/beta-catenin pathway was activated in human AA samples. The cytosinephosphate- guanine islands in the SOST gene promoter showed significantly higher methylation in human AA samples compared with controls. Incubation of vascular smooth muscle cells with the demethylating agent 5-azacytidine resulted in upregulation of SOST, suggesting that SOST is epigenetically regulated. Conclusions-This study identifies that SOST is expressed in the aorta and downregulated in human AA possibly because of epigenetic silencing. Upregulating SOST inhibits AA and atherosclerosis development, with potential important implications for treating these vascular diseases.
The association between serum uric acid and blood pressure in different age groups in a healthy Chinese cohort
- Cheng, Wenjuan, Wen, Shiling, Wang, Yutang, Qian, Zhiping, Tan, Yuyao, Li, Hongying, Hou, Yueli, Hu, Haiyang, Golledge, Jonathan, Yang, Guang
- Authors: Cheng, Wenjuan , Wen, Shiling , Wang, Yutang , Qian, Zhiping , Tan, Yuyao , Li, Hongying , Hou, Yueli , Hu, Haiyang , Golledge, Jonathan , Yang, Guang
- Date: 2017
- Type: Text , Journal article
- Relation: Medicine (United States) Vol. 96, no. 50 (2017), p.1-6
- Relation: http://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
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- Description: High serum uric acid (sUA) has been reported to be a risk factor for hypertension however, whether this is the case for all age groups is not clear. We examined the association between sUA concentrations and systolic and diastolic blood pressure (SBP and DBP) in different age groups in a cohort of healthy Chinese participants. A total of 1082 healthy participants aged from 41 to 70 years were included. sUA concentration was measured by the uricase-peroxidase method. SBP and DBP were assessed using mercury sphygmomanometry. Hypertension was defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg. Hyperuricemia (HUA) was defined as sUA concentration of >7 mg/dL in men and >6 mg/dL in women. The association between sUA concentration and SBP and DBP was examined using Pearson's correlation test, multivariate linear regression, and logistic regression analysis. The prevalence of hypertension and HUA increased with age (P < .001). Hypertension was more common in participants that had HUA than in those that did not (38.95% vs 30.16%, P = .02). Higher sUA was significantly associated with higher SBP and DBP in the 41- to 50-year-old participants (SBP, β = 0.35, P < .001; DBP, β = .29, P < .001; after adjustment for age, sex, total cholesterol, estimated glomerular filtration rate, and fasting plasma glucose). HUA was also a risk factor for hypertension in this age group (odds ratio 1.425, 95% confidence interval, 1.217-1.668, P < .001). There was no association between sUA concentration and SBP and DBP in the other age groups. In this population of healthy Chinese participants, sUA concentration was positively associated with hypertension only in the 41- to 50-year-old group. Lowering uric acid in this age group may help to reduce the incidence of hypertension.
- Authors: Cheng, Wenjuan , Wen, Shiling , Wang, Yutang , Qian, Zhiping , Tan, Yuyao , Li, Hongying , Hou, Yueli , Hu, Haiyang , Golledge, Jonathan , Yang, Guang
- Date: 2017
- Type: Text , Journal article
- Relation: Medicine (United States) Vol. 96, no. 50 (2017), p.1-6
- Relation: http://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: High serum uric acid (sUA) has been reported to be a risk factor for hypertension however, whether this is the case for all age groups is not clear. We examined the association between sUA concentrations and systolic and diastolic blood pressure (SBP and DBP) in different age groups in a cohort of healthy Chinese participants. A total of 1082 healthy participants aged from 41 to 70 years were included. sUA concentration was measured by the uricase-peroxidase method. SBP and DBP were assessed using mercury sphygmomanometry. Hypertension was defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg. Hyperuricemia (HUA) was defined as sUA concentration of >7 mg/dL in men and >6 mg/dL in women. The association between sUA concentration and SBP and DBP was examined using Pearson's correlation test, multivariate linear regression, and logistic regression analysis. The prevalence of hypertension and HUA increased with age (P < .001). Hypertension was more common in participants that had HUA than in those that did not (38.95% vs 30.16%, P = .02). Higher sUA was significantly associated with higher SBP and DBP in the 41- to 50-year-old participants (SBP, β = 0.35, P < .001; DBP, β = .29, P < .001; after adjustment for age, sex, total cholesterol, estimated glomerular filtration rate, and fasting plasma glucose). HUA was also a risk factor for hypertension in this age group (odds ratio 1.425, 95% confidence interval, 1.217-1.668, P < .001). There was no association between sUA concentration and SBP and DBP in the other age groups. In this population of healthy Chinese participants, sUA concentration was positively associated with hypertension only in the 41- to 50-year-old group. Lowering uric acid in this age group may help to reduce the incidence of hypertension.
Stage 1 hypertension and risk of cardiovascular disease mortality in United States adults with or without diabetes
- Authors: Wang, Yutang
- Date: 2022
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 40, no. 4 (2022), p. 794-803
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Objective: This study aimed to investigate the association of S1 hypertension, classified according to the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guideline, with cardiovascular disease (CVD) mortality in adults with or without diabetes from the general United States population.Methods:This cohort study included 40 518 United States adults (including 3555 with diabetes) naive to antihypertensive drugs who attended the National Health and Nutrition Examination Surveys from 1988 to 2014.Results:Participants were followed up for 489 679 person-years (mean follow-up, 12.1 years) with 1569 CVD deaths being recorded. S1 hypertension was neither associated with an increased CVD mortality risk in the whole cohort nor in participants with or without diabetes after full adjustment. In age-stratified analyses, compared with normal BP, S1 hypertension was associated with increased CVD mortality in young adults, unrelated to CVD mortality in midlife, and associated with lower CVD mortality in the elderly. In older participants (
- Authors: Wang, Yutang
- Date: 2022
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 40, no. 4 (2022), p. 794-803
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Objective: This study aimed to investigate the association of S1 hypertension, classified according to the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guideline, with cardiovascular disease (CVD) mortality in adults with or without diabetes from the general United States population.Methods:This cohort study included 40 518 United States adults (including 3555 with diabetes) naive to antihypertensive drugs who attended the National Health and Nutrition Examination Surveys from 1988 to 2014.Results:Participants were followed up for 489 679 person-years (mean follow-up, 12.1 years) with 1569 CVD deaths being recorded. S1 hypertension was neither associated with an increased CVD mortality risk in the whole cohort nor in participants with or without diabetes after full adjustment. In age-stratified analyses, compared with normal BP, S1 hypertension was associated with increased CVD mortality in young adults, unrelated to CVD mortality in midlife, and associated with lower CVD mortality in the elderly. In older participants (
Definition, prevalence, and risk factors of low sex hormone-binding globulin in US adults
- Authors: Wang, Yutang
- Date: 2021
- Type: Text , Journal article
- Relation: Journal of Clinical Endocrinology and Metabolism Vol. 106, no. 10 (2021), p. E3946-E3956
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- Description: Context: Lower sex hormone-binding globulin (SHBG) is associated with many diseases including cardiovascular disease, cancer, polycystic ovarian syndrome, arthritis, and liver disease. However, the definition of low SHBG and its prevalence in US adults are unknown. Objective: To define low SHBG and to determine its prevalence and risk factors in US adults. Design, Setting, and Participants: This cohort study included adults ≥20 years from the US National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016 who had fasting serum SHBG. Exposures: NHANES coverage during 2013-2016. Main Outcomes Measures: Definition, prevalence, and risk factors of low SHBG. Results: This study included 4093 adults (weighted sample size of 204 789 616) with a mean (SD) age of 47.5 (17.0) years. In a "healthy"reference sub-cohort of 1477 adults, low SHBG was defined as SHBG<12.3 nmol/L in men<50 years, <23.5 nmol/L in men≥50 years, <14.5 nmol/L in women<30 years, and <21.9 nmol/L in women≥30 years. The estimated US national prevalence of low SHBG was 3.3% in men, 2.7% in women, and 3.0% overall. Risk factors for this condition in both men and women included higher body mass index, diabetes, ethnicity (being other than Hispanic, non-Hispanic black, or non-Hispanic white), chronic obstructive pulmonary disease, coronary heart disease, and smoking. Conclusions: This study established the criteria for low SHBG among US adults. The estimated US national prevalence of low SHBG was 3.3% in men and 2.7% in women. © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.
- Authors: Wang, Yutang
- Date: 2021
- Type: Text , Journal article
- Relation: Journal of Clinical Endocrinology and Metabolism Vol. 106, no. 10 (2021), p. E3946-E3956
- Full Text:
- Reviewed:
- Description: Context: Lower sex hormone-binding globulin (SHBG) is associated with many diseases including cardiovascular disease, cancer, polycystic ovarian syndrome, arthritis, and liver disease. However, the definition of low SHBG and its prevalence in US adults are unknown. Objective: To define low SHBG and to determine its prevalence and risk factors in US adults. Design, Setting, and Participants: This cohort study included adults ≥20 years from the US National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016 who had fasting serum SHBG. Exposures: NHANES coverage during 2013-2016. Main Outcomes Measures: Definition, prevalence, and risk factors of low SHBG. Results: This study included 4093 adults (weighted sample size of 204 789 616) with a mean (SD) age of 47.5 (17.0) years. In a "healthy"reference sub-cohort of 1477 adults, low SHBG was defined as SHBG<12.3 nmol/L in men<50 years, <23.5 nmol/L in men≥50 years, <14.5 nmol/L in women<30 years, and <21.9 nmol/L in women≥30 years. The estimated US national prevalence of low SHBG was 3.3% in men, 2.7% in women, and 3.0% overall. Risk factors for this condition in both men and women included higher body mass index, diabetes, ethnicity (being other than Hispanic, non-Hispanic black, or non-Hispanic white), chronic obstructive pulmonary disease, coronary heart disease, and smoking. Conclusions: This study established the criteria for low SHBG among US adults. The estimated US national prevalence of low SHBG was 3.3% in men and 2.7% in women. © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.
Mouse models of intracranial aneurysm
- Wang, Yutang, Emeto, Theophilus, Lee, James, Marshman, Laurence, Moran, Corey, Seto, Sai-wang, Golledge, Jonathan
- Authors: Wang, Yutang , Emeto, Theophilus , Lee, James , Marshman, Laurence , Moran, Corey , Seto, Sai-wang , Golledge, Jonathan
- Date: 2014
- Type: Text , Journal article
- Relation: Brain Pathology Vol. 25, no. (2014), p. 237-247
- Relation: http://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Subarachnoid hemorrhage secondary to rupture of an intracranial aneurysm is a highly lethal medical condition. Current management strategies for unruptured intracranial aneurysms involve radiological surveillance and neurosurgical or endovascular interventions. There is no pharmacological treatment available to decrease the risk of aneurysm rupture and subsequent subarachnoid hemorrhage. There is growing interest in the pathogenesis of intracranial aneurysm focused on the development of drug therapies to decrease the incidence of aneurysm rupture. The study of rodent models of intracranial aneurysms has the potential to improve our understanding of intracranial aneurysm development and progression. This review summarizes current mouse models of intact and ruptured intracranial aneurysms and discusses the relevance of these models to human intracranial aneurysms. The article also reviews the importance of these models in investigating the molecular mechanisms involved in the disease. Finally, potential pharmaceutical targets for intracranial aneurysm suggested by previous studies are discussed. Examples of potential drug targets include matrix metalloproteinases, stromal cell-derived factor-1, tumor necrosis factor-α, the renin-angiotensin system and the β-estrogen receptor. An agreed clear, precise and reproducible definition of what constitutes an aneurysm in the models would assist in their use to better understand the pathology of intracranial aneurysm and applying findings to patients
- Description: Subarachnoid hemorrhage secondary to rupture of an intracranial aneurysm is a highly lethal medical condition. Current management strategies for unruptured intracranial aneurysms involve radiological surveillance and neurosurgical or endovascular interventions. There is no pharmacological treatment available to decrease the risk of aneurysm rupture and subsequent subarachnoid hemorrhage. There is growing interest in the pathogenesis of intracranial aneurysm focused on the development of drug therapies to decrease the incidence of aneurysm rupture. The study of rodent models of intracranial aneurysms has the potential to improve our understanding of intracranial aneurysm development and progression. This review summarizes current mouse models of intact and ruptured intracranial aneurysms and discusses the relevance of these models to human intracranial aneurysms. The article also reviews the importance of these models in investigating the molecular mechanisms involved in the disease. Finally, potential pharmaceutical targets for intracranial aneurysm suggested by previous studies are discussed. Examples of potential drug targets include matrix metalloproteinases, stromal cell-derived factor-1, tumor necrosis factor-
- Authors: Wang, Yutang , Emeto, Theophilus , Lee, James , Marshman, Laurence , Moran, Corey , Seto, Sai-wang , Golledge, Jonathan
- Date: 2014
- Type: Text , Journal article
- Relation: Brain Pathology Vol. 25, no. (2014), p. 237-247
- Relation: http://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Subarachnoid hemorrhage secondary to rupture of an intracranial aneurysm is a highly lethal medical condition. Current management strategies for unruptured intracranial aneurysms involve radiological surveillance and neurosurgical or endovascular interventions. There is no pharmacological treatment available to decrease the risk of aneurysm rupture and subsequent subarachnoid hemorrhage. There is growing interest in the pathogenesis of intracranial aneurysm focused on the development of drug therapies to decrease the incidence of aneurysm rupture. The study of rodent models of intracranial aneurysms has the potential to improve our understanding of intracranial aneurysm development and progression. This review summarizes current mouse models of intact and ruptured intracranial aneurysms and discusses the relevance of these models to human intracranial aneurysms. The article also reviews the importance of these models in investigating the molecular mechanisms involved in the disease. Finally, potential pharmaceutical targets for intracranial aneurysm suggested by previous studies are discussed. Examples of potential drug targets include matrix metalloproteinases, stromal cell-derived factor-1, tumor necrosis factor-α, the renin-angiotensin system and the β-estrogen receptor. An agreed clear, precise and reproducible definition of what constitutes an aneurysm in the models would assist in their use to better understand the pathology of intracranial aneurysm and applying findings to patients
- Description: Subarachnoid hemorrhage secondary to rupture of an intracranial aneurysm is a highly lethal medical condition. Current management strategies for unruptured intracranial aneurysms involve radiological surveillance and neurosurgical or endovascular interventions. There is no pharmacological treatment available to decrease the risk of aneurysm rupture and subsequent subarachnoid hemorrhage. There is growing interest in the pathogenesis of intracranial aneurysm focused on the development of drug therapies to decrease the incidence of aneurysm rupture. The study of rodent models of intracranial aneurysms has the potential to improve our understanding of intracranial aneurysm development and progression. This review summarizes current mouse models of intact and ruptured intracranial aneurysms and discusses the relevance of these models to human intracranial aneurysms. The article also reviews the importance of these models in investigating the molecular mechanisms involved in the disease. Finally, potential pharmaceutical targets for intracranial aneurysm suggested by previous studies are discussed. Examples of potential drug targets include matrix metalloproteinases, stromal cell-derived factor-1, tumor necrosis factor-
The penetration of methanol into bovine cardiac and hepatic tissues is faster than ethanol and formalin
- Steicke, Michelle, Yang, Guang, Dinh, Tam, Dunster-Jones, Matthew, Sargisson, Owen, Ahmady, Farah, Golledge, Jonathan, Wang, Yutang
- Authors: Steicke, Michelle , Yang, Guang , Dinh, Tam , Dunster-Jones, Matthew , Sargisson, Owen , Ahmady, Farah , Golledge, Jonathan , Wang, Yutang
- Date: 2018
- Type: Text , Journal article
- Relation: European Journal of Histochemistry Vol. 62, no. 1 (2018), p. 98-104
- Relation: http://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Methanol, ethanol and formalin are commonly used as fixatives to preserve biological tissues from decay in the preparation of histological sections. Fixation of the inner layers of the tissue depends on the ability of the fixative to diffuse into the tissue. It is unknown whether methanol penetrates tissues at similar rates to other fixatives. This study aimed to compare the penetration rates of methanol, ethanol and formalin into bovine heart and liver tissues. The penetration distance and tissue shrinkage or expansion were measured by analysing the digital images of tissue before and after immersion in different fixatives for 1, 2, 6 or 10 h. Data were analysed using two-way ANOVA, followed by Bonferroni’s post-hoc test. The penetration distance of methanol was significantly greater in both heart and liver tissues compared with that of ethanol (N=4, P<0.001). Methanol or ethanol immersion led to similar shrinkage of both tissues (P>0.05). The penetration rate of formalin was similar to that of ethanol in both tissues however it was significantly slower than methanol (N=4, P<0.005 in the heart; P<0.001 in the liver). The mean penetration coefficients of methanol, formalin and ethanol in the heart tissue were 2.609, 1.994 and 1.801, respectively, and 3.012, 2.153 and 2.113, respectively, in the liver tissue. The penetration coefficient of methanol was significantly greater than that of ethanol or formalin in both tissues (P<0.001 for each comparison). In conclusion, methanol penetrates tissue significantly faster than ethanol and formalin.
- Authors: Steicke, Michelle , Yang, Guang , Dinh, Tam , Dunster-Jones, Matthew , Sargisson, Owen , Ahmady, Farah , Golledge, Jonathan , Wang, Yutang
- Date: 2018
- Type: Text , Journal article
- Relation: European Journal of Histochemistry Vol. 62, no. 1 (2018), p. 98-104
- Relation: http://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: Methanol, ethanol and formalin are commonly used as fixatives to preserve biological tissues from decay in the preparation of histological sections. Fixation of the inner layers of the tissue depends on the ability of the fixative to diffuse into the tissue. It is unknown whether methanol penetrates tissues at similar rates to other fixatives. This study aimed to compare the penetration rates of methanol, ethanol and formalin into bovine heart and liver tissues. The penetration distance and tissue shrinkage or expansion were measured by analysing the digital images of tissue before and after immersion in different fixatives for 1, 2, 6 or 10 h. Data were analysed using two-way ANOVA, followed by Bonferroni’s post-hoc test. The penetration distance of methanol was significantly greater in both heart and liver tissues compared with that of ethanol (N=4, P<0.001). Methanol or ethanol immersion led to similar shrinkage of both tissues (P>0.05). The penetration rate of formalin was similar to that of ethanol in both tissues however it was significantly slower than methanol (N=4, P<0.005 in the heart; P<0.001 in the liver). The mean penetration coefficients of methanol, formalin and ethanol in the heart tissue were 2.609, 1.994 and 1.801, respectively, and 3.012, 2.153 and 2.113, respectively, in the liver tissue. The penetration coefficient of methanol was significantly greater than that of ethanol or formalin in both tissues (P<0.001 for each comparison). In conclusion, methanol penetrates tissue significantly faster than ethanol and formalin.