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Coronary artery disease : Why we should consider the Y chromosome

- Molina, Elsa, Clarence, Elyse, Ahmady, Farah, Chew, Guatsiew, Charchar, Fadi

  • Authors: Molina, Elsa , Clarence, Elyse , Ahmady, Farah , Chew, Guatsiew , Charchar, Fadi
  • Date: 2016
  • Type: Text , Journal article , Review
  • Relation: Heart Lung and Circulation Vol. 25, no. 8 (Aug 2016), p. 791-801
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality globally. In the last few years our understanding of the genetic and molecular mechanisms that promote CAD in individuals has increased with the advent of the genome era. This complex inflammatory disease has well-defined environmental risk factors. However, in the last 10 years, studies including genome-wide association studies (GWAS) have clearly demonstrated a genetic influence on CAD. Recently, studies on the human Y chromosome have also demonstrated that genetic variation within the male-specific region of the Y chromosome (MSY) could play a part in determining cardiovascular risk in men, confirming the notion that the increased risk for CAD in men cannot be fully explained through common CAD risk factors. Here, we review the literature about the pathophysiology of CAD, its potential causes and environmental risk factors known so far. Furthermore, we review the genetics of CAD, especially the latest discoveries regarding the implication of the Y chromosome, the most underexplored portion of the human genome to date, highlighting methods and difficulties arising in this research field, and discussing the importance of considering the Y chromosome in CAD research.

Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies

- Morris, Andrew, Le, Thu, Wu, Haojia, Akbarov, Artur, van der Most, Peter, Hemani, Gibran, Smith, George, Mahajan, Anubha, Gaulton, Kyle, Nadkarni, Girish, Valladares-Salgado, Adan, Wacher-Rodarte, Niels, Mychaleckyj, Josyf, Dueker, Nicole, Guo, Xiuqing, Hai, Yang, Haessler, Jeffrey, Kamatani, Yoichiro, Stilp, Adrienne, Zhu, Gu, Cook, James, Arnlov, Johan, Blanton, Susan, de Borst, Martin, Bottinger, Erwin, Buchanan, Thomas, Cechova, Sylvia, Charchar, Fadi, Chu, Pei-Lun, Damman, Jeffrey, Eales, James, Gharavi, Ali, Giedraitis, Vilmantas, Heath, Andrew, Ipp, Eli, Kiryluk, Krzysztof, Kramer, Holly, Kubo, Michiaki, Larsson, Anders, Lindgren, Cecilia, Lu, Yingchang, Madden, Pamela, Montgomery, Grant, Papanicolaou, George, Raffel, Leslie, Sacco, Ralph, Sanchez, Elena, Stark, Holger, Sundstrom, Johan, Taylor, Kent, Xiang, Anny, Zivkovic, Aleksandra, Lind, Lars, Ingelsson, Erik, Martin, Nicholas, Whitfield, John, Cai, Jianwen, Laurie, Cathy, Okada, Yukinori, Matsuda, Koichi, Kooperberg, Charles, Chen, Yii-Der, Rundek, Tatjana, Rich, Stephen, Loos, Ruth, Parra, Esteban, Cruz, Miguel, Rotter, Jerome, Snieder, Harold, Tomaszewski, Maciej, Humphreys, Benjamin, Franceschini, Nora

Plasma lipocalin-2/NGAL is stable over 12 weeks and is not modulated by exercise or dieting

- Nakai, Michael, Prestes, Priscilla, O’Brien, Brendan, Charchar, Fadi, Marques, Francine

  • Authors: Nakai, Michael , Prestes, Priscilla , O’Brien, Brendan , Charchar, Fadi , Marques, Francine
  • Date: 2021
  • Type: Text , Journal article
  • Relation: Scientific Reports Vol. 11, no. 1 (2021), p.
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  • Description: Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18–55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention (r = 0.743, P < 0.0001). This suggests that circulating LCN2 expression are stable over a period of at least 12 weeks and is not modifiable by diet and exercise. © 2021, The Author(s). *Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Priscilla Prestes, Brendan O'Brien, Fadi Charchar and Francine Marques” is provided in this record** .

Consumption of a low glycaemic index diet in late life extends lifespan of Nalb/c mice with differential effects on DNA damage

- Nankervis, Scott, Mitchell, Jenée, Charchar, Fadi, McGlynn, Maree, Lewandowski, Paul

  • Authors: Nankervis, Scott , Mitchell, Jenée , Charchar, Fadi , McGlynn, Maree , Lewandowski, Paul
  • Date: 2013
  • Type: Text , Journal article
  • Relation: Longevity & Healthspan. 2(4) p. 1-13
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  • Description: Background Caloric restriction is known to extend the lifespan of all organisms in which it has been tested. Consequently, current research is investigating the role of various foods to improve health and lifespan. The role of various diets has received less attention however, and in some cases may have more capacity to improve health and longevity than specific foods alone. We examined the benefits to longevity of a low glycaemic index (GI) diet in aged Balb/c mice and examined markers of oxidative stress and subsequent effects on telomere dynamics. Results In an aged population of mice, a low GI diet extended average lifespan by 12%, improved glucose tolerance and had impressive effects on amelioration of oxidative damage to DNA in white blood cells. Telomere length in quadriceps muscle showed no improvement in the dieted group, nor was telomerase reactivated. Conclusion The beneficial effects of a low GI diet are evident from the current study and although the impact to telomere dynamics late in life is minimal, we expect that earlier intervention with a low GI diet would provide significant improvement in health and longevity with associated effects to telomere homeostasis.

Metabolic syndrome is associated with similar long-term prognosis in those living with and without obesity : an analysis of 45 615 patients from the nationwide LIPIDOGRAM 2004-2015 studies

- Osadnik, Kamila, Osadnik, Tadeusz, Gierlotka, Marek, Windak, Adam, Tomasik, Tomasz, Mastej, Miroslaw, Kuras, Agnieszka, Jóźwiak, Kacper, Penson, Peter, Lip, Gregory, Mikhailidis, Dimitri, Toth, Peter, Catapano, Alberico, Ray, Kausik, Howard, George, Tomaszewski, Maclej, Charchar, Fadi, Sattar, Naveed, Williams, Bryan, MacDonald, Thomas, Banach, Maclej, Jóźwiak, Jacek

  • Authors: Osadnik, Kamila , Osadnik, Tadeusz , Gierlotka, Marek , Windak, Adam , Tomasik, Tomasz , Mastej, Miroslaw , Kuras, Agnieszka , Jóźwiak, Kacper , Penson, Peter , Lip, Gregory , Mikhailidis, Dimitri , Toth, Peter , Catapano, Alberico , Ray, Kausik , Howard, George , Tomaszewski, Maclej , Charchar, Fadi , Sattar, Naveed , Williams, Bryan , MacDonald, Thomas , Banach, Maclej , Jóźwiak, Jacek
  • Date: 2023
  • Type: Text , Journal article
  • Relation: European Journal of Preventive Cardiology Vol. 30, no. 12 (2023), p. 1195-1204
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  • Description: Aims: We aimed to evaluate the association between metabolic syndrome (MetS) and long-term all-cause mortality. Methods and results: The LIPIDOGRAM studies were carried out in the primary care in Poland in 2004, 2006, and 2015. MetS was diagnosed based on the National Cholesterol Education Program, Adult Treatment Panel III (NCEP/ATP III), and Joint Interim Statement (JIS) criteria. The cohort was divided into four groups: non-obese patients without MetS, obese patients without MetS, non-obese patients with MetS, and obese patients with MetS. Differences in all-cause mortality were analysed using Kaplan-Meier and Cox regression analyses. A total of 45 615 participants were enrolled (mean age 56.3, standard deviation: 11.8 years; 61.7% female). MetS was diagnosed in 14 202 (31%) by NCEP/ATP III criteria and 17 216 (37.7%) by JIS criteria. Follow-up was available for 44 620 (97.8%, median duration 15.3 years) patients. MetS was associated with increased mortality risk among the obese {hazard ratio, HR: 1.88 [95% confidence interval (CI) 1.79-1.99] and HR: 1.93 [95% CI 1.82-2.04], according to NCEP/ATP III and JIS criteria, respectively} and non-obese individuals [HR: 2.11 (95% CI 1.85-2.40) and 1.7 (95% CI 1.56-1.85) according to NCEP/ATP III and JIS criteria, respectively]. Obese patients without MetS had a higher mortality risk than non-obese patients without MetS [HR: 1.16 (95% CI 1.10-1.23) and HR: 1.22 (95% CI 1.15-1.30), respectively in subgroups with NCEP/ATP III and JIS criteria applied]. Conclusions: MetS is associated with increased all-cause mortality risk in non-obese and obese patients. In patients without MetS, obesity remains significantly associated with mortality. The concept of metabolically healthy obesity should be revised. © 2023 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved.

Salt Loading in Canola Oil Fed SHRSP Rats Induces Endothelial Dysfunction

- Papazzo, Annateresa, Conlan, Xavier, Lexis, Louise, Charchar, Fadi, Lewandowski, Paul

  • Authors: Papazzo, Annateresa , Conlan, Xavier , Lexis, Louise , Charchar, Fadi , Lewandowski, Paul
  • Date: 2013
  • Type: Text , Journal article
  • Relation: PLoS ONE Vol. 8, no. 6 (2013), p.
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  • Description: This study aimed to determine if 50 days of canola oil intake in the absence or presence of salt loading affects: (1) antioxidant and oxidative stress markers, (2) aortic mRNA of NADPH oxidase (NOX) subunits and superoxide dismutase (SOD) isoforms and (3) endothelial function in SHRSP rats. SHRSP rats were fed a diet containing 10 wt/wt% soybean oil or 10 wt/wt% canola oil, and given tap water or water containing 1% NaCl for 50 days. Without salt, canola oil significantly increased RBC SOD, plasma cholesterol and triglycerides, aortic p22phox, NOX2 and CuZn-SOD mRNA, and decreased RBC glutathione peroxidase activity. With salt, canola oil reduced RBC SOD and catalase activity, LDL-C, and p22phox mRNA compared with canola oil alone, whereas plasma malondialdehyde (MDA) was reduced and RBC MDA and LDL-C were higher. With salt, the canola oil group had significantly reduced endothelium-dependent vasodilating responses to ACh and contractile responses to norepinephrine compared with the canola oil group without salt and to the WKY rats. These results indicate that ingestion of canola oil increases O2 - generation, and that canola oil ingestion in combination with salt leads to endothelial dysfunction in the SHRSP model. © 2013 Papazzo et al.
  • Description: 2003011096

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
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  • 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.

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

- Pattaro, C, Teumer, A, Gorski, M, Chu, A.Y., Li, M, Mijatovic, V, Garnaas, M, Tin, A, Charchar, Fadi

  • Authors: Pattaro, C , Teumer, A , Gorski, M , Chu, A.Y. , Li, M , Mijatovic, V , Garnaas, M , Tin, A , Charchar, Fadi
  • Date: 2016
  • Type: Text , Journal article
  • Relation: Nature Communications Vol. 7, no. (2016), p. 1-19
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  • Description: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. © 2016, Nature Publishing Group. All rights reserved. Please note that there are two hundred and six authors for this article and we have included only the Federation University Australia affiliate.

Tripartite motif-containing 55 identified as functional candidate for spontaneous cardiac hypertrophy in the rat locus cardiac mass 22

- Prestes, Priscilla, Marques, Francine, Lopez-Campos, Guillermo, Booth, Scott, McGlynn, Maree, Lewandowski, Paul, Delbridge, Lea, Harrap, Stephen, Charchar, Fadi

  • Authors: Prestes, Priscilla , Marques, Francine , Lopez-Campos, Guillermo , Booth, Scott , McGlynn, Maree , Lewandowski, Paul , Delbridge, Lea , Harrap, Stephen , Charchar, Fadi
  • Date: 2016
  • Type: Text , Journal article
  • Relation: Journal of Hypertension Vol. 34, no. 5 (May 2016), p. 950-958
  • Relation: http://purl.org/au-research/grants/nhmrc/1034371
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  • Description: Background:Left ventricular (LV) hypertrophy is a risk factor for cardiovascular death, but the genetic factors determining LV size and predisposition to hypertrophy are not well understood. We have previously linked the quantitative trait locus cardiac mass 22 (Cm22) on chromosome 2 with cardiac hypertrophy independent of blood pressure in the spontaneously hypertensive rat. From an original cross of spontaneously hypertensive rat with F344 rats, we derived a normotensive polygenic model of spontaneous cardiac hypertrophy, the hypertrophic heart rat (HHR) and its control strain, the normal heart rat (NHR).Methods and results:To identify the genes and molecular mechanisms underlying spontaneous LV hypertrophy we sequenced the HHR genome with special focus on quantitative trait locus Cm22. For correlative analyses of function, we measured global RNA transcripts in LV of neonatal HHR and NHR and 198 neonatal rats of an HHRxNHR F2 crossbred population. Only one gene within locus Cm22 was differentially expressed in the parental generation: tripartite motif-containing 55 (Trim55), with mRNA downregulation in HHR (P<0.05) and reduced protein expression. Trim55 mRNA levels were negatively correlated with LV mass in the F2 cross (r=-0.16, P=0.025). In exon nine of Trim55 in HHR, we found one missense mutation that functionally alters protein structure. This mutation was strongly associated with Trim55 mRNA expression in F2 rats (F=10.35, P<0.0001). Similarly, in humans, we found reduced Trim55 expression in hearts of subjects with idiopathic dilated cardiomyopathy.Conclusion:Our study suggests that the Trim55 gene, located in Cm22, is a novel candidate gene for polygenic LV hypertrophy independent of blood pressure.

Involvement of human monogenic cardiomyopathy genes in experimental polygenic cardiac hypertrophy

- Prestes, Priscilla, Marques, Francine, Lopez-Campos, Guillermo, Lewandowski, Paul, Delbridge, Lea, Charchar, Fadi, Harrap, Stephen

  • Authors: Prestes, Priscilla , Marques, Francine , Lopez-Campos, Guillermo , Lewandowski, Paul , Delbridge, Lea , Charchar, Fadi , Harrap, Stephen
  • Date: 2018
  • Type: Text , Journal article
  • Relation: Physiological Genomics Vol. 50, no. 9 (2018), p. 680-687
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  • Description: Hypertrophic cardiomyopathy thickens heart muscles, reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure, to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole genome of 13-wk-old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at 5 ages (2 days old and 4, 13, 33, and 50 wk old) compared with human idiopathic dilated cardiomyopathy data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-day-old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in noncoding regions of HHR and NHR. We found 29 genes differentially expressed in at least 1 age. Genes encoding desmoglein 2 (Dsg2) and transthyretin (Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.

A guide to the short, long and circular RNAs in hypertension and cardiovascular disease

- Prestes, Priscilla, Maier, Michelle, Woods, Bradley, Charchar, Fadi

  • Authors: Prestes, Priscilla , Maier, Michelle , Woods, Bradley , Charchar, Fadi
  • Date: 2020
  • Type: Text , Journal article , Review
  • Relation: International Journal of Molecular Sciences Vol. 21, no. 10 (2020)
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  • Description: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in adults in developed countries. CVD encompasses many diseased states, including hypertension, coronary artery disease and atherosclerosis. Studies in animal models and human studies have elucidated the contribution of many genetic factors, including non-coding RNAs. Non-coding RNAs are RNAs not translated into protein, involved in gene expression regulation post-transcriptionally and implicated in CVD. Of these, circular RNAs (circRNAs) and microRNAs are relevant. CircRNAs are created by the back-splicing of pre-messenger RNA and have been underexplored as contributors to CVD. These circRNAs may also act as biomarkers of human disease, as they can be extracted from whole blood, plasma, saliva and seminal fluid. CircRNAs have recently been implicated in various disease processes, including hypertension and other cardiovascular disease. This review article will explore the promising and emerging roles of circRNAs as potential biomarkers and therapeutic targets in CVD, in particular hypertension. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

DNA copy number variations – Do these big mutations have a big effect on cardiovascular risk?

- Prestes, Priscilla, Maier, Michelle, Charchar, Fadi

  • Authors: Prestes, Priscilla , Maier, Michelle , Charchar, Fadi
  • Date: 2019
  • Type: Text , Journal article , Editorial
  • Relation: International Journal of Cardiology Vol. 298, no. (2019), p. 116-117
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  • Description: In simple terms, copy number variations or CNVs are replications or deletions in the DNA which, in humans, changes it from the normal number of two gene copies. These CNVs are caused by inherited or de novo structural changes such as duplications, insertions or deletions of repeated portions of genetic material (Fig. 1). These duplications can vary from one to ten or more copies and range in size from 50 DNA base pairs to several million [1]. Since their discovery in 1987 by Nakamura et al. [2], when they were initially named variable number tandem repeats, many studies have investigated their association with rare and common human diseases. Throughout evolution, some of these changes in copy number were beneficial such as the globin gene number duplication, while others such as the CNVs that cause Huntington's disease were not. In 2004, two landmark studies by Iafrate et al. [3] and Sebat et al. [4] found that large-scale copy-number variations, ranging in size from 100 kb to 2 Mb are common throughout the human genome, and that a high proportion of them are in known genes. These findings roused several association studies between CNVs and disease

Hyperuricemia is independently associated with hypertension in men under 60 years in a general Chinese population

- Qian, Tingting, Sun, Hui, Xu, Qun, Charchar, Fadi, Wang, Yutang

  • Authors: Qian, Tingting , Sun, Hui , Xu, Qun , Charchar, Fadi , Wang, Yutang
  • Date: 2021
  • Type: Text , Journal article
  • Relation: Journal of Human Hypertension Vol. 35, no. 11 (2021), p. 1020-1028
  • Relation: https://purl.org/au-research/grants/nhmrc/1062671
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  • Description: Hyperuricemia has been associated with hypertension, however, whether this association exists across all decades of adult life is unknown. This study aimed to assess the association between hyperuricemia and hypertension in relation to age. This retrospective cross-sectional study included a total of 22,556 adult Chinese people who attended Health Physical Examination in a Chinese hospital. Participants were aged between 18 and 95 years (mean [standard deviation], 45.4 [14.0]). Serum uric acid levels and blood pressure were measured. Associations between serum uric acid and blood pressure, and between hyperuricemia and hypertension diagnosis were analyzed using linear or logistic regression, adjusting for confounding risk factors including age, sex, total cholesterol, high-density lipoprotein cholesterol, and fasting blood glucose. Sub-analysis was stratified by age and sex. Before adjustment, high serum uric acid was associated with higher systolic blood pressure (β = 0.214, P < 0.001) and higher diastolic blood pressure (β = 0.271, P < 0.001). Hyperuricemia was associated with hypertension diagnosis (OR, 1.763; 95% CI, 1.635–1.901; P < 0.001) in an unadjusted analysis. These findings remained significant after adjusting for confounding factors. Sub-analysis suggested that the association between uric acid and blood pressure was weaker in older age groups and the association between hyperuricemia and hypertension was limited to people under 60 years. Hyperuricemia was independently associated with hypertension diagnosis in men but not in women, and the independent association between hyperuricemia and hypertension only presented in men under 60 years. This study suggests that hyperuricemia is independently associated with hypertension in Chinese men under 60 years. © 2020, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature. **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Fadi Charchar and Yutang Wang” is provided in this record**

Abnormal microRNA expression in cardiac hypertrophy and the regulation of the Endog gene

- Quarrell, Sean, Marques, Francine, Jayaswal, Vivek, Curl, Claire, Nankervis, Scott, Yang, Jean, Delbridge, Lea, Harrap, Stephen, Charchar, Fadi

  • Authors: Quarrell, Sean , Marques, Francine , Jayaswal, Vivek , Curl, Claire , Nankervis, Scott , Yang, Jean , Delbridge, Lea , Harrap, Stephen , Charchar, Fadi
  • Date: 2012
  • Type: Text , Journal article
  • Relation: Heart, Lung and Circulation Vol. 21, no. Supplement 1 (2012), p. s7
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  • Description: A deficiency in the gene for endonuclease G (Endog) was recently described as a genetic determinant of cardiac hypertrophy. The mechanisms involved in the regulation of Endog, however, are still to be elucidated. Therefore we hypothesised that Endog, being regulated by small regulatory non-coding RNAs called microRNAs (miRNAs), could contribute to the cardiac hypertrophy of the Hypertrophic Heart Rat (HHR), a human polygenic model of cardiac hypertrophy. From birth the HHR has less and smaller cardiomyocytes, which leads to hypertrophy and cardiac failure later in life. In this study, we examined genome-wide miRNA expression by Agilent Rat miRNA Microarray Kit Release 16.0 and Endog mRNA levels by real-time PCR in the left ventricle of neonatal HHR compared to age-matched rats from its authentic control, the Normal Heart Rat (NHR). Endog mRNA was significantly under-expressed in the HHR (fold change=−4.7; P=0.0001). Sixty-seven miRNAs (FDR P<0.05 and fold change>1.1) were differentially expressed between HHR and NHR (n=16). We then performed an in silico analysis to predict the miRNAs that are able to bind to the 3′ untranslated region of Endog mRNA, and therefore could regulate Endog levels. We discovered that the miRNAs let-7b, miR-338 and miR-347 are predicted to bind to Endog mRNA. Functional studies are being undertaken to determine whether these miRNAs can regulate Endog mRNA levels in vitro and their role in the pathological processes leading to cardiac hypertrophy. These miRNAs could be a new target for the prevention and treatment of cardiac hypertrophy in humans

Contribution of microRNA to pathological fibrosis in cardiorenal syndrome : Impact of uremic toxins

- Rana, Indrajeetsinh, Kompa, Andrew, Skommer, Joanna, Wang, Bing, Lekawanvijit, Suree, Kelly, Darren, Krum, Henry, Charchar, Fadi

  • Authors: Rana, Indrajeetsinh , Kompa, Andrew , Skommer, Joanna , Wang, Bing , Lekawanvijit, Suree , Kelly, Darren , Krum, Henry , Charchar, Fadi
  • Date: 2015
  • Type: Text , Journal article
  • Relation: Physiological Reports Vol. 3, no. 4 (2015), p. 1-15
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  • Description: Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and micro- RNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis. © 2015 The Authors.

MicroRNAs mediate the cardioprotective effect of angiotensin-converting enzyme inhibition in acute kidney injury

- Rana, Indrajeetsinh, Velkoska, Elena, Patel, Sheila, Burrell, Louise, Charchar, Fadi

  • Authors: Rana, Indrajeetsinh , Velkoska, Elena , Patel, Sheila , Burrell, Louise , Charchar, Fadi
  • Date: 2015
  • Type: Text , Journal article
  • Relation: American Journal of Physiology - Renal Physiology Vol. 309, no. 11 (2015), p. F943-F954
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  • Description: Cardiovascular disease, including cardiac hypertrophy, is common in patients with kidney disease and can be partially attenuated using blockers of the renin-angiotensin system (RAS). It is unknown whether cardiac microRNAs contribute to the pathogenesis of cardiac hypertrophy or to the protective effect of RAS blockade in kidney disease. Using a subtotal nephrectomy rat model of kidney injury, we investigated changes in cardiac microRNAs that are known to have direct target genes involved in the regulation of apoptosis, fibrosis, and hypertrophy. The effect of treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac microRNAs was also investigated. Kidney injury led to a significant increase in cardiac microRNA-212 and mi- croRNA-132 expression. Ramipril reduced cardiac hypertrophy, attenuated the increase in microRNA-212 and microRNA-132, and significantly increased microRNA-133 and microRNA-1 expression. There was altered expression of caspase-9, B cell lymphoma-2, transforming growth factor-β, fibronectin 1, collagen type 1A1, and forkhead box protein O3, which are all known to be involved in the regulation of apoptosis, fibrosis, and hypertrophy in cardiac cells while being targets for the above microRNAs. ACE inhibitor treatment increased expression of microRNA-133 and microRNA-1. The inhibitory action of ACE inhibitor treatment on increased cardiac NADPH oxidase isoform 1 expression after subtotal nephrectomy surgery suggests that inhibition of oxidative stress is also one of mechanism of ACE inhibitor-mediated cardioprotection. These finding suggests the involvement of microRNAs in the cardioprotective action of ACE inhibition in acute renal injury, which is mediated through an inhibitory action on profibrotic and proapoptotic target genes and stimulatory action on antihypertrophic and antiapoptotic target genes. © 2015 the American Physiological Society. Funding: APP1048285; NHMRC; National Health and Medical Research Council

Circulating microRNAs and hypertension - From new insights into blood pressure regulation to biomarkers of cardiovascular risk

- Romaine, Simon, Charchar, Fadi, Samani, Nilesh, Tomaszewski, Maciej

  • Authors: Romaine, Simon , Charchar, Fadi , Samani, Nilesh , Tomaszewski, Maciej
  • Date: 2016
  • Type: Text , Journal article
  • Relation: Current Opinion in Pharmacology Vol. 27, no. (2016), p. 1-7
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: Hypertension is a leading cause of cardiovascular morbidity and mortality worldwide, yet the molecular mechanisms underpinning the development of high blood pressure remain incompletely understood. MicroRNAs are small, non-coding RNA molecules approximately 22 nucleotides in length that act as post-transcriptional regulators of gene expression. We highlight, through a review of recent literature, that studies on circulating microRNAs have provided novel insights into blood pressure regulation. They have also complemented tissue-based and animal-based experiments in shedding new light on our understanding of established pathways in hypertension, such as the renin-angiotensin system. Despite a number of challenges, we believe microRNAs herald particular potential in becoming effective biomarkers of target-organ damage in hypertension. © 2016 Elsevier Ltd. All rights reserved.

Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics

- Rowland, Joshua, Akbarov, Artur, Eales, James, Xu, Xiaoguang, Dormer, John, Guo, Hui, Denniff, Matthew, Jiang, Xiao, Ranjzad, Parisa, Nazgiewicz, Alicja, Prestes, Priscilla, Antczak, Andrzej, Szulinska, Monika, Wise, Ingrid, Zukowska-Szczechowska, Ewa, Bogdanski, Pawel, Woolf, Adrian, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej

  • Authors: Rowland, Joshua , Akbarov, Artur , Eales, James , Xu, Xiaoguang , Dormer, John , Guo, Hui , Denniff, Matthew , Jiang, Xiao , Ranjzad, Parisa , Nazgiewicz, Alicja , Prestes, Priscilla , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Zukowska-Szczechowska, Ewa , Bogdanski, Pawel , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
  • Date: 2019
  • Type: Text , Journal article
  • Relation: Kidney International Vol. 95, no. 3 (2019), p. 624-635
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  • Description: Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.

MicroRNAs in a hypertrophic heart : From foetal life to adulthood

- Sadiq, Shahzad, Crowley, Tamsyn, Charchar, Fadi, Sanigorski, Andrew, Lewandowski, Paul

  • Authors: Sadiq, Shahzad , Crowley, Tamsyn , Charchar, Fadi , Sanigorski, Andrew , Lewandowski, Paul
  • Date: 2017
  • Type: Text , Journal article
  • Relation: Biological Reviews Vol. 92, no. 3 (2017), p. 1314-1331
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  • Description: The heart is the first organ to form and undergoes adaptive remodelling with age. Ventricular hypertrophy is one such adaptation, which allows the heart to cope with an increase in cardiac demand. This adaptation is necessary as part of natural growth from foetal life to adulthood. It may also occur in response to resistance in blood flow due to various insults on the heart and vessels that accumulate with age. The heart can only compensate to this increase in workload to a certain extent without losing its functional architecture, ultimately resulting in heart failure. Many genes have been implicated in cardiac hypertrophy, however none have been shown conclusively to be responsible for pathological cardiac hypertrophy. MicroRNAs offer an alternative mechanism for cellular regulation by altering gene expression. Since 1993 when the function of a non-coding DNA sequence was first discovered in the model organism Caenorhabditis elegans, many microRNAs have been implicated in having a central role in numerous physiological and pathological cellular processes. The level of control these antisense oligonucleotides offer can often be exploited to manipulate the expression of target genes. Moreover, altered levels of microRNAs can serve as diagnostic biomarkers, with the prospect of diagnosing a disease process as early as during foetal life. Therefore, it is vital to ascertain and investigate the function of microRNAs that are involved in heart development and subsequent ventricular remodelling. Here we present an overview of the complicated network of microRNAs and their target genes that have previously been implicated in cardiogenesis and hypertrophy. It is interesting to note that microRNAs in both of these growth processes can be of possible remedial value to counter a similar disease pathophysiology.

Addressing global disparities in blood pressure control : perspectives of the International Society of Hypertension

- Schutte, Aletta, Jafar, Tazeen, Poulter, Neil, Damasceno, Albertino, Khan, Nadia, Nilsson, Peter, Alsaid, Jafar, Neupane, Dinesh, Kario, Kazuomi, Beheiry, Hind, Brouwers, Sofie, Burger, Dylan, Charchar, Fadi, Cho, Myeong-Chan, Guzik, Tomasz, Haji Al-Saedi, Ghazi, Ishaq, Muhammad, Itoh, Hiroshi, Jones, Erika, Khan, Taskeen, Kokubo, Yoshihiro, Kotruchin, Praew, Muxfeldt, Elizabeth, Odili, Augustine, Patil, Mansi, Ralapanawa, Udaya, Romero, Cesar, Schlaich, Markus, Shehab, Abdulla, Mooi, Ching

  • Authors: Schutte, Aletta , Jafar, Tazeen , Poulter, Neil , Damasceno, Albertino , Khan, Nadia , Nilsson, Peter , Alsaid, Jafar , Neupane, Dinesh , Kario, Kazuomi , Beheiry, Hind , Brouwers, Sofie , Burger, Dylan , Charchar, Fadi , Cho, Myeong-Chan , Guzik, Tomasz , Haji Al-Saedi, Ghazi , Ishaq, Muhammad , Itoh, Hiroshi , Jones, Erika , Khan, Taskeen , Kokubo, Yoshihiro , Kotruchin, Praew , Muxfeldt, Elizabeth , Odili, Augustine , Patil, Mansi , Ralapanawa, Udaya , Romero, Cesar , Schlaich, Markus , Shehab, Abdulla , Mooi, Ching
  • Date: 2023
  • Type: Text , Journal article , Review
  • Relation: Cardiovascular Research Vol. 119, no. 2 (2023), p. 381-409
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  • Description: Raised blood pressure (BP) is the leading cause of preventable death in the world. Yet, its global prevalence is increasing, and it remains poorly detected, treated, and controlled in both high- and low-resource settings. From the perspective of members of the International Society of Hypertension based in all regions, we reflect on the past, present, and future of hypertension care, highlighting key challenges and opportunities, which are often region-specific. We report that most countries failed to show sufficient improvements in BP control rates over the past three decades, with greater improvements mainly seen in some high-income countries, also reflected in substantial reductions in the burden of cardiovascular disease and deaths. Globally, there are significant inequities and disparities based on resources, sociodemographic environment, and race with subsequent disproportionate hypertension-related outcomes. Additional unique challenges in specific regions include conflict, wars, migration, unemployment, rapid urbanization, extremely limited funding, pollution, COVID-19-related restrictions and inequalities, obesity, and excessive salt and alcohol intake. Immediate action is needed to address suboptimal hypertension care and related disparities on a global scale. We propose a Global Hypertension Care Taskforce including multiple stakeholders and societies to identify and implement actions in reducing inequities, addressing social, commercial, and environmental determinants, and strengthening health systems implement a well-designed customized quality-of-care improvement framework. © 2022 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology. **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliate “Fadi Charchar” is provided in this record**