Neurogenic hypertension : Revelations from genome-wide gene expression profiling
- Marques, Francine, Morris, Brian
- Authors: Marques, Francine , Morris, Brian
- Date: 2012
- Type: Text , Journal article
- Relation: Current Hypertension Reports Vol. 14, no. 6 (2012), p. 485-491
- Full Text: false
- Reviewed:
- Description: There is now good evidence for a role of the sympathetic nervous system in the etiology of essential hypertension in humans. Although genetic variation is expected to underlie the elevated sympathetic outflow in this complex polygenic condition, only limited information has emerged from classic molecular genetic studies. Recently, progress has been made in understanding neurogenic aspects by determination of global alterations in gene expression in key brain regions of animal models of neurogenic hypertension. Such genome-wide expression studies in the hypothalamus and brainstem support roles for factors such as neuronal nitric oxide synthase, inflammation and reactive oxygen species. A role for non-coding RNAs such as microRNAs, and epigenetic alterations await exploration. Ongoing novel approaches should provide a better understanding of the processes responsible for the increased sympathetic outflow in animal models, as well as essential hypertension in humans. Such information may lead to better therapies for neurogenic hypertension in humans. © Springer Science+Business Media, LLC 2012.
- Description: 2003010573
Signatures of miR-181a on the renal transcriptome and blood pressure
- Marques, Francine, Romaine, Simon, Denniff, Matthew, Eales, James, Dormer, John, Garrelds, Ingrid, Wojnar, Lukasz, Musialik, Katarzyna, Duda-Raszewska, Barbara, Kiszka, Bartlomiej, Duda, Magdalena, Morris, Brian, Samani, Nilesh, Jan Danser, Jan, Bogdanski, Pawel, Zukowska-Szczechowska, Ewa, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Marques, Francine , Romaine, Simon , Denniff, Matthew , Eales, James , Dormer, John , Garrelds, Ingrid , Wojnar, Lukasz , Musialik, Katarzyna , Duda-Raszewska, Barbara , Kiszka, Bartlomiej , Duda, Magdalena , Morris, Brian , Samani, Nilesh , Jan Danser, Jan , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2015
- Type: Text , Journal article
- Relation: Molecular Medicine Vol. 21, no. (2015), p. 739-748
- Full Text: false
- Reviewed:
- Description: MicroRNA-181a binds to the 3’ untranslated region of messenger RNA (mRNA) for renin, a rate-limiting enzyme of the renin-angiotensin system. Our objective was to determine whether this molecular interaction translates into a clinically meaningful effect on blood pressure and whether circulating miR-181a is a measurable proxy of blood pressure. In 200 human kidneys from the TRANScriptome of renaL humAn TissuE (TRANSLATE) study, renal miR-181a was the sole negative predictor of renin mRNA and a strong correlate of circulating miR-181a. Elevated miR-181a levels correlated positively with systolic and diastolic blood pressure in TRANSLATE, and this association was independent of circulating renin. The association between serum miR-181a and systolic blood pressure was replicated in 199 subjects from the Genetic Regulation of Arterial Pressure of Humans In the Community (GRAPHIC) study. Renal immunohistochemistry and in situ hybridization showed that colocalization of miR-181a and renin was most prominent in collecting ducts where renin is not released into the systemic circulation. Analysis of 69 human kidneys characterized by RNA sequencing revealed that miR-181a was associated with downregulation of four mitochondrial pathways and upregulation of 41 signaling cascades of adaptive immunity and inflammation. We conclude that renal miR-181a has pleiotropic effects on pathways relevant to blood pressure regulation and that circulating levels of miR-181a are both a measurable proxy of renal miR-181a expression and a novel biochemical correlate of blood pressure.
Measurement of absolute copy number variation reveals association with essential hypertension
- Marques, Francine, Prestes, Priscilla, Pinheiro, Leonardo, Scurrah, Katrina, Emslie, Kerry, Tomaszewski, Maciej, Harrap, Stephen, Charchar, Fadi
- Authors: Marques, Francine , Prestes, Priscilla , Pinheiro, Leonardo , Scurrah, Katrina , Emslie, Kerry , Tomaszewski, Maciej , Harrap, Stephen , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: BMC Medical Genomics Vol. 7, no. (2014), p. 1-8
- Full Text:
- Reviewed:
- Description: Background: The role of copy number variation (CNV) has been poorly explored in essential hypertension in part due to technical difficulties in accurately assessing absolute numbers of DNA copies. Droplet digital PCR (ddPCR) provides a powerful new approach to CNV quantitation. The aim of our study was to investigate whether CNVs located in regions previously associated with blood pressure (BP) variation in genome-wide association studies (GWAS) were associated with essential hypertension by the use of ddPCR. Methods: Using a "power of extreme" approach, we quantified nucleic acids using ddPCR in white subjects from the Victorian Family Heart Study with extremely high (n = 96) and low (n = 92) SBP, providing power equivalent to 1714 subjects selected at random. Results: A deletion of the CNVs esv27061 and esv2757747 on chromosome 1p13.2 was significantly more prevalent in extreme high BP subjects after adjustment for age, body mass index and sex (12.6% vs. 2.2%; P = 0.013). Conclusions: Our data suggests that CNVs within regions identified in previous GWAS may play a role in human essential hypertension.
- Authors: Marques, Francine , Prestes, Priscilla , Pinheiro, Leonardo , Scurrah, Katrina , Emslie, Kerry , Tomaszewski, Maciej , Harrap, Stephen , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: BMC Medical Genomics Vol. 7, no. (2014), p. 1-8
- Full Text:
- Reviewed:
- Description: Background: The role of copy number variation (CNV) has been poorly explored in essential hypertension in part due to technical difficulties in accurately assessing absolute numbers of DNA copies. Droplet digital PCR (ddPCR) provides a powerful new approach to CNV quantitation. The aim of our study was to investigate whether CNVs located in regions previously associated with blood pressure (BP) variation in genome-wide association studies (GWAS) were associated with essential hypertension by the use of ddPCR. Methods: Using a "power of extreme" approach, we quantified nucleic acids using ddPCR in white subjects from the Victorian Family Heart Study with extremely high (n = 96) and low (n = 92) SBP, providing power equivalent to 1714 subjects selected at random. Results: A deletion of the CNVs esv27061 and esv2757747 on chromosome 1p13.2 was significantly more prevalent in extreme high BP subjects after adjustment for age, body mass index and sex (12.6% vs. 2.2%; P = 0.013). Conclusions: Our data suggests that CNVs within regions identified in previous GWAS may play a role in human essential hypertension.
MicroRNAs in essential hypertension and blood pressure regulation
- Marques, Francine, Charchar, Fadi
- Authors: Marques, Francine , Charchar, Fadi
- Date: 2015
- Type: Text , Book chapter
- Relation: Advances in Experimental Medicine and Biology p. 215-235
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: Unravelling the complete genetic predisposition to high blood pressure (BP) has proven to be challenging. This puzzle and the fact that coding regions of the genome account for less than 2 % of the entire human DNA support the hypothesis that mechanisms besides coding genes are likely to contribute to BP regulation. Non-coding RNAs, especially microRNAs, are emerging as key players of transcription regulation in both health and disease states. They control basic functions in virtually all cell types relevant to the cardiovascular system and, thus, a direct involvement with BP regulation is highly probable. Here we review the literature about microRNAs associated with regulation of BP and hypertension, highlighting investigations, methodology and difficulties arising in the field. These molecules are being studied for exploitation in diagnostics, prognostics and therapeutics in many diseases. There have been some studies that examined biological fl uid microRNAs as biomarkers for hypertension, but most remain inconclusive due to the small sample sizes and differences in methodological standardisation. Fewer studies have analysed tissue microRNA levels in vascular smooth muscle cells and the kidney. Others focused on the interaction between single nucleotide polymorphisms and microRNA binding sites. Studies in animals have shown that angiotensin II, high- salt diet and exercise change microRNA levels in hypertension. Treatment of spontaneously hypertensive rats with a miR-22 inhibitor and treatment of hypertensive Schlager BPH/2J mice with a miR-181a mimic decreased their BP. This supports the use of microRNAs as therapeutic targets in hypertension, and future studies should test the use of other microRNAs found in human association studies. In conclusion, there is a clear need of increased pace of human, animal and functional studies to help us understand the multifaceted roles of microRNAs as critical regulators of the development and physiology of BP. © Springer International Publishing Switzerland 2015. Funding Details: APP1052659, NHMRC, National Heart Foundation of Australia Funding Details: PF12M6785, National Heart Foundation of Australia
Deficiency of MicroRNA-181a results in transcriptome-wide cell-specific changes in the kidney and increases blood pressure
- Paterson, Madeleine, Jackson, Kristy, Dona, Malathi, Farrugia, Gabriella, Visniauskas, Bruna, Watson, Anna, Johnson, Chad, Prieto, Minolfa, Evans, Roger, Charchar, Fadi, Pinto, Alexander, Marques, Francine, Head, Geoffrey
- Authors: Paterson, Madeleine , Jackson, Kristy , Dona, Malathi , Farrugia, Gabriella , Visniauskas, Bruna , Watson, Anna , Johnson, Chad , Prieto, Minolfa , Evans, Roger , Charchar, Fadi , Pinto, Alexander , Marques, Francine , Head, Geoffrey
- Date: 2021
- Type: Text , Journal article
- Relation: Hypertension Vol. 78, no. 5 (Nov 2021), p. 1322-1334
- Full Text:
- Reviewed:
- Description: MicroRNA miR-181a is downregulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here, we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a KO (knockout) mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radiotelemetry probes were implanted in 12-week-old C57BL/6J WT (wild type) and miR-181a/b-1 KO mice. Systolic and diastolic BP were 4- to 5-mm Hg higher in KO compared with WT mice over 24 hours (P<0.01). Compared with WT mice, renal renin was higher in the juxtaglomerular cells of KO mice. BP was similar in WT mice on a high- (3.1%) versus low- (0.3%) sodium diet (+0.4 +/- 0.8 mm Hg), but KO mice showed salt sensitivity (+3.3 +/- 0.8 mm Hg; P<0.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA sequencing in 6699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, and Smad4. We observed upregulation of pathways related to the immune system, inflammatory response, reactive oxygen species, and nerve development, consistent with higher tyrosine hydroxylase in the kidney. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.
- Authors: Paterson, Madeleine , Jackson, Kristy , Dona, Malathi , Farrugia, Gabriella , Visniauskas, Bruna , Watson, Anna , Johnson, Chad , Prieto, Minolfa , Evans, Roger , Charchar, Fadi , Pinto, Alexander , Marques, Francine , Head, Geoffrey
- Date: 2021
- Type: Text , Journal article
- Relation: Hypertension Vol. 78, no. 5 (Nov 2021), p. 1322-1334
- Full Text:
- Reviewed:
- Description: MicroRNA miR-181a is downregulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here, we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a KO (knockout) mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radiotelemetry probes were implanted in 12-week-old C57BL/6J WT (wild type) and miR-181a/b-1 KO mice. Systolic and diastolic BP were 4- to 5-mm Hg higher in KO compared with WT mice over 24 hours (P<0.01). Compared with WT mice, renal renin was higher in the juxtaglomerular cells of KO mice. BP was similar in WT mice on a high- (3.1%) versus low- (0.3%) sodium diet (+0.4 +/- 0.8 mm Hg), but KO mice showed salt sensitivity (+3.3 +/- 0.8 mm Hg; P<0.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA sequencing in 6699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, and Smad4. We observed upregulation of pathways related to the immune system, inflammatory response, reactive oxygen species, and nerve development, consistent with higher tyrosine hydroxylase in the kidney. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.
Lifestyle management of hypertension : International Society of Hypertension position paper endorsed by the World Hypertension League and European Society of Hypertension
- Charchar, Fadi, Prestes, Priscilla, Mills, Charlotte, Ching, Siew, Neupane, Dinesh, Marques, Francine, Sharman, James, Vogt, Liffert, Burrell, Louise, Korostovtseva, Lyudmila, Zec, Manja, Patil, Mansi, Schultz, Martin, Wallen, Matthew, Renna, Nicolás, Islam, Sheikh, Hiremath, Swapnil, Gyeltshen, Tshewang, Chia, Yook-Chin, Gupta, Abhinav, Schutte, Aletta, Klein, Britt, Borghi, Claudio, Browning, Colette, Czesnikiewicz-Guzik, Marta, Lee, Hae-Young, Itoh, Hiroshi, Miura, Katsuyuki, Akinnibosun, Olutope, Shane Thomas
- Authors: Charchar, Fadi , Prestes, Priscilla , Mills, Charlotte , Ching, Siew , Neupane, Dinesh , Marques, Francine , Sharman, James , Vogt, Liffert , Burrell, Louise , Korostovtseva, Lyudmila , Zec, Manja , Patil, Mansi , Schultz, Martin , Wallen, Matthew , Renna, Nicolás , Islam, Sheikh , Hiremath, Swapnil , Gyeltshen, Tshewang , Chia, Yook-Chin , Gupta, Abhinav , Schutte, Aletta , Klein, Britt , Borghi, Claudio , Browning, Colette , Czesnikiewicz-Guzik, Marta , Lee, Hae-Young , Itoh, Hiroshi , Miura, Katsuyuki , Akinnibosun, Olutope , Shane Thomas
- Date: 2024
- Type: Text , Journal article
- Relation: Journal of hypertension Vol. 42, no. 1 (2024), p. 23-49
- Full Text:
- Reviewed:
- Description: Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools. **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliates “Fadi Charchar, Priscilla Prestes, Britt Klein, Colette Browning, Olutope Akinnibosun and Shane Thomas” are provided in this record**
- Description: Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools. **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliates “Fadi Charchar, Priscilla Prestes, Britt Klein, Colette Browning, Olutope Akinnibossun and Shane Thomas” are provided in this record**
- Authors: Charchar, Fadi , Prestes, Priscilla , Mills, Charlotte , Ching, Siew , Neupane, Dinesh , Marques, Francine , Sharman, James , Vogt, Liffert , Burrell, Louise , Korostovtseva, Lyudmila , Zec, Manja , Patil, Mansi , Schultz, Martin , Wallen, Matthew , Renna, Nicolás , Islam, Sheikh , Hiremath, Swapnil , Gyeltshen, Tshewang , Chia, Yook-Chin , Gupta, Abhinav , Schutte, Aletta , Klein, Britt , Borghi, Claudio , Browning, Colette , Czesnikiewicz-Guzik, Marta , Lee, Hae-Young , Itoh, Hiroshi , Miura, Katsuyuki , Akinnibosun, Olutope , Shane Thomas
- Date: 2024
- Type: Text , Journal article
- Relation: Journal of hypertension Vol. 42, no. 1 (2024), p. 23-49
- Full Text:
- Reviewed:
- Description: Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools. **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliates “Fadi Charchar, Priscilla Prestes, Britt Klein, Colette Browning, Olutope Akinnibosun and Shane Thomas” are provided in this record**
- Description: Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools. **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliates “Fadi Charchar, Priscilla Prestes, Britt Klein, Colette Browning, Olutope Akinnibossun and Shane Thomas” are provided in this record**
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