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Increased expression of telomere-regulating genes in endurance athletes with long leukocyte telomeres

  • Authors: Denham, Joshua , O'Brien, Brendan , Prestes, Priscilla , Brown, Nicholas , Charchar, Fadi
  • Date: 2015
  • Type: Text , Journal article
  • Relation: Journal of Applied Physiology Vol. 120, no. 2 (2015), p. 148-158
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative (V) over dotO(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.

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

  • 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.

Genetic variation within the Y chromosome is not associated with histological characteristics of the atherosclerotic carotid artery or aneurysmal wall

  • Authors: Haitjema, Saskia , van Setten, Jessica , Eales, James , van der Laan, Sander , Gandin, Ilaria , de Vries, Jean-Paul , de Borst, Gert , Pasterkamp, Gerard , Asselbergs, Folkert , Charchar, Fadi , Wilson, James , de Jager, Saskia , Tomaszewski, Maciej , den Ruijter, Hester
  • Date: 2017
  • Type: Text , Journal article
  • Relation: Atherosclerosis Vol. 259, no. (2017), p. 114-119
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  • Description: Background and aims: Haplogroup I, a common European paternal lineage of the Y chromosome, is associated with increased risk of coronary artery disease in British men. It is unclear whether this haplogroup or any other haplogroup on the Y chromosome is associated with histological characteristics of the diseased vessel wall in other vascular manifestations of cardiovascular diseases showing a male preponderance. Methods: We examined Dutch men undergoing either carotid endarterectomy from the Athero-Express biobank (AE, n = 1217) or open aneurysm repair from the Aneurysm-Express biobank (AAA, n = 393). Upon resolving the Y chromosome phylogeny, each man was assigned to one of the paternal lineages based on combinations of single nucleotide polymorphisms of the male-specific region of the Y chromosome. We examined the associations between the Y chromosome and the histological characteristics of the carotid plaque and aneurysm wall, including lipid content, leukocyte infiltration and intraplaque haemorrhage, in all men. Results: A majority of men were carriers of either haplogroup I (AE: 28% AAA: 24%) or haplogroup R (AE: 59% AAA: 61%). We found no association between Y chromosomal haplogroups and histological characteristics of plaque collected from carotid arteries or tissue specimens of aneurysms. Moreover, the distribution of frequency for all Y chromosomal haplogroups in both cohorts was similar to that of a general population of Dutch men. Conclusions: Our data show that genetic variation on the Y chromosome is not associated with histological characteristics of the plaques from carotid arteries or specimens of aneurysms in men of Dutch origin. © 2017 Elsevier B.V.

Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure

Aortic augmentation index in endurance athletes : A role for cardiorespiratory fitness

  • Authors: Denham, Joshua , Brown, Nicholas , Tomaszewski, Maciej , Williams, Bryan , O’Brien, Brendan , Charchar, Fadi
  • Date: 2016
  • Type: Text , Journal article
  • Relation: European Journal of Applied Physiology Vol. 116, no. 8 (2016), p. 1537-1544
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: Purpose: Endurance exercise improves cardiovascular health and reduces mortality risk. Augmentation index (AIx) reflects adverse loading exerted on the heart and large arteries and predicts future cardiovascular disease. The purpose of this study was to establish whether endurance athletes possess lower AIx and aortic blood pressure compared to healthy controls, and to determine the association between AIx and cardiorespiratory fitness. Methods: Forty-six endurance athletes and 43 healthy controls underwent central BP and AIx measurements by non-invasive applanation tonometry before a maximal exercise test. Peak oxygen uptake (V˙ O 2 peak) was assessed by pulmonary analysis. Results: Relative to controls, athletes had significantly lower brachial diastolic blood pressure (BP, −4.8 mmHg, p < 0.01), central systolic BP (−3.5 mmHg, p = 0.07), and AIx at a heart rate of 75 beats min−1 (AIx@75, −11.9 %, p < 0.001). No AIx@75 differences were observed between athletes and controls when adjusted for age and V˙ O 2 peak [athletes vs controls mean (%) ± SE: −6.9 ± 2.2 vs −5.7 ± 2.3, p = 0.76]. Relative to men with low V˙ O 2 peak, those with moderate and high V˙ O 2 peak had lower age-adjusted AIx@75 (p < 0.001). In women, those with high V˙ O 2 peak had lower AIx@75 than those with low and moderate V˙ O 2 peak (p < 0.01). Conclusions: The lower AIx@75 in endurance athletes is partly mediated by V˙ O 2 peak. While an inverse relationship between AIx@75 and V˙ O 2 peak was found in men, women with the highest V˙ O 2 peak possessed lowest AIx@75 compared to females with moderate or poor cardiorespiratory fitness. We recommend aerobic training aimed at achieving a minimum V˙ O 2 peak of 45 ml kg−1 min−1 to decrease the risk of future cardiovascular events and all-cause mortality.
  • Description: Purpose: Endurance exercise improves cardiovascular health and reduces mortality risk. Augmentation index (AIx) reflects adverse loading exerted on the heart and large arteries and predicts future cardiovascular disease. The purpose of this study was to establish whether endurance athletes possess lower AIx and aortic blood pressure compared to healthy controls, and to determine the association between AIx and cardiorespiratory fitness. Methods: Forty-six endurance athletes and 43 healthy controls underwent central BP and AIx measurements by non-invasive applanation tonometry before a maximal exercise test. Peak oxygen uptake (V˙ O 2 peak) was assessed by pulmonary analysis. Results: Relative to controls, athletes had significantly lower brachial diastolic blood pressure (BP, −4.8 mmHg, p < 0.01), central systolic BP (−3.5 mmHg, p = 0.07), and AIx at a heart rate of 75 beats min−1 (AIx@75, −11.9 %, p < 0.001). No AIx@75 differences were observed between athletes and controls when adjusted for age and V˙ O 2 peak [athletes vs controls mean (%) ± SE: −6.9 ± 2.2 vs −5.7 ± 2.3, p = 0.76]. Relative to men with low V˙ O 2 peak, those with moderate and high V˙ O 2 peak had lower age-adjusted AIx@75 (p < 0.001). In women, those with high V˙ O 2 peak had lower AIx@75 than those with low and moderate V˙ O 2 peak (p < 0.01). Conclusions: The lower AIx@75 in endurance athletes is partly mediated by V˙ O 2 peak. While an inverse relationship between AIx@75 and V˙ O 2 peak was found in men, women with the highest V˙ O 2 peak possessed lowest AIx@75 compared to females with moderate or poor cardiorespiratory fitness. We recommend aerobic training aimed at achieving a minimum V˙ O 2 peak of 45 ml kg−1 min−1 to decrease the risk of future cardiovascular events and all-cause mortality. © 2016, Springer-Verlag Berlin Heidelberg.

A novel Y-specific long non-coding RNA associated with cellular lipid accumulation in HepG2 cells and Atherosclerosis-related genes

  • Authors: Molina, Elsa , Chew, Guat , Myers, Stephen , Clarence, Elyse , Eales, James , Tomaszewski, Maciej , Charchar, Fadi
  • Date: 2017
  • Type: Text , Journal article
  • Relation: Scientific Reports Vol. 7, no. 1 (2017), p. 1-12
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.

Cardiac telomere length in heart development, function, and disease

  • Authors: Booth, Scott , Charchar, Fadi
  • Date: 2017
  • Type: Text , Journal article , Review
  • Relation: Physiological Genomics Vol. 49, no. 7 (2017), p. 368-384
  • Relation: http://purl.org/au-research/grants/nhmrc/1034371
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  • Description: Telomeres are repetitive nucleoprotein structures at chromosome ends, and a decrease in the number of these repeats, known as a reduction in telomere length (TL), triggers cellular senescence and apoptosis. Heart disease, the worldwide leading cause of death, often results from the loss of cardiac cells, which could be explained by decreases in TL. Due to the cell-specific regulation of TL, this review focuses on studies that have measured telomeres in heart cells and critically assesses the relationship between cardiac TL and heart function. There are several lines of evidence that have identified rapid changes in cardiac TL during the onset and progression of heart disease as well as at critical stages of development. There are also many factors, such as the loss of telomeric proteins, oxidative stress, and hypoxia, that decrease cardiac TL and heart function. In contrast, antioxidants, calorie restriction, and exercise can prevent both cardiac telomere attrition and the progression of heart disease. TL in the heart is also indicative of proliferative potential and could facilitate the identification of cells suitable for cardiac rejuvenation. Although these findings highlight the involvement of TL in heart function, there are important questions regarding the validity of animal models, as well as several confounding factors, that need to be considered when interpreting results and planning future research. With these in mind, elucidating the telomeric mechanisms involved in heart development and the transition to disease holds promise to prevent cardiac dysfunction and potentiate regeneration after injury. © 2017 the American Physiological Society.

Experimental and human evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin NGAL ) in the development of cardiac hypertrophy and heart failure

A meta-analysis of gene expression signatures of blood pressure and hypertension

  • Authors: Charchar, Fadi
  • Date: 2015
  • Type: Text , Journal article
  • Relation: PLoS Genetics Vol. 11, no. 3 (2015), p. 1-29
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  • Description: Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension. **Please note that there are multiple authors for this article therefore only the name of the Federation University Australia affiliate is provided in this record**

Telomere dynamics during aging in polygenic left ventricular hypertrophy

  • Authors: Marques, Francine , Booth, Scott , Prestes, Priscilla , Curl, Claire , Delbridge, Lea , Lewandowski, Paul , Harrap, Stephen , Charchar, Fadi
  • Date: 2016
  • Type: Text , Journal article
  • Relation: Physiological Genomics Vol. 48, no. 1 (2016), p. 42-49
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  • Description: Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk. © 2016 the American Physiological Society.

MicroRNAs in essential hypertension and blood pressure regulation

  • 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
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  • 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

Genetics of blood pressure : Time to curate the collection

  • Authors: Harrap, Stephen , Charchar, Fadi
  • Date: 2017
  • Type: Text , Journal article , Editorial
  • Relation: Journal of Hypertension Vol. 35, no. 7 (2017), p. 1360-1362
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  • Description: The genetics of blood pressure (BP) is all about discovery and understanding, but it is certainly not for the faint hearted. Despite heroic effort, the question we posed nearly 15 years ago [1] regarding the whereabouts of BP genes remains largely unanswered.

Body mass index is negatively associated with telomere length : A collaborative cross-sectional meta-analysis of 87 observational studies

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

  • 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

Telomere length maintenance and cardio-metabolic disease prevention through exercise training

  • Authors: Denham, Joshua , O'Brien, Brendan , Charchar, Fadi
  • Date: 2016
  • Type: Text , Journal article , Review
  • Relation: Sports Medicine Vol. 46, no. 9 (2016), p. 1213-1237
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: Telomeres are tandem repeat DNA sequences located at distal ends of chromosomes that protect against genomic DNA degradation and chromosomal instability. Excessive telomere shortening leads to cellular senescence and for this reason telomere length is a marker of biological age. Abnormally short telomeres may culminate in the manifestation of a number of cardio-metabolic diseases. Age-related cardio-metabolic diseases attributable to an inactive lifestyle, such as obesity, type 2 diabetes mellitus and cardiovascular disease, are associated with short leukocyte telomeres. Exercise training prevents and manages the symptoms of many cardio-metabolic diseases whilst concurrently maintaining telomere length. The positive relationship between exercise training, physical fitness and telomere length raises the possibility of a mediating role of telomeres in chronic disease prevention via exercise. Further elucidation of the underpinning molecular mechanisms of how exercise maintains telomere length should provide crucial information on how physical activity can be best structured to combat the chronic disease epidemic and improve the human health span. Here, we synthesise and discuss the current evidence on the impact of physical activity and cardiorespiratory fitness on telomere dynamics. We provide the molecular mechanisms with a known role in exercise-induced telomere length maintenance and highlight unexplored, alternative pathways ripe for future investigations.

Epigenetic changes in leukocytes after 8 weeks of resistance exercise training

  • Authors: Denham, Joshua , Marques, Francine , Bruns, Emma , O'Brien, Brendan , Charchar, Fadi
  • Date: 2016
  • Type: Text , Journal article
  • Relation: European Journal of Applied Physiology Vol. 116, no. 6 (2016), p. 1245-1253
  • Relation: http://purl.org/au-research/grants/nhmrc/1009490
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  • Description: PURPOSE: Regular engagement in resistance exercise training elicits many health benefits including improvement to muscular strength, hypertrophy and insulin sensitivity, though the underpinning molecular mechanisms are poorly understood. The purpose of this study was to determine the influence 8 weeks of resistance exercise training has on leukocyte genome-wide DNA methylation and gene expression in healthy young men. METHODS: Eight young (21.1 +/- 2.2 years) men completed one repetition maximum (1RM) testing before completing 8 weeks of supervised, thrice-weekly resistance exercise training comprising three sets of 8-12 repetitions with a load equivalent to 80 % of 1RM. Blood samples were collected at rest before and after the 8-week training intervention. Genome-wide DNA methylation and gene expression were assessed on isolated leukocyte DNA and RNA using the 450K BeadChip and HumanHT-12 v4 Expression BeadChip (Illumina), respectively. RESULTS: Resistance exercise training significantly improved upper and lower body strength concurrently with diverse genome-wide DNA methylation and gene expression changes (p

Leukocyte telomere length variation due to DNA extraction method

  • Authors: Denham, Joshua , Marques, Francine , Charchar, Fadi
  • Date: 2014
  • Type: Text , Journal article
  • Relation: BMC research notes Vol. 7, no. (2014), p. 877
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  • Description: Telomere length is indicative of biological age. Shorter telomeres have been associated with several disease and health states. There are inconsistencies throughout the literature amongst relative telomere length measured by quantitative PCR (qPCR) and different extraction methods or kits used. We quantified whole-blood leukocyte telomere length using the telomere to single copy gene (T/S) ratio by qPCR in 20 young (18-25 yrs) men after extracting DNA using three common extraction methods: Lahiri and Nurnberger (high salt) method, PureLink Genomic DNA Mini kit (Life Technologies) and QiaAmp DNA Mini kit (Qiagen). Telomere length differences of DNA extracted from the three extraction methods was assessed by one-way analysis of variance (ANOVA).

Renal nerves contribute to hypertension in Schlager BPH/2J mice

  • Authors: Gueguen, Cindy , Jackson, Kristy , Marques, Francine , Eikelis, Nina , Phillips, Sarah , Stevenson, Emily , Charchar, Fadi , Lambert, Gavin , Davern, Pamela , Head, Geoffrey
  • Date: 2019
  • Type: Text , Journal article
  • Relation: Hypertension Research Vol. 42, no. 3 (2019), p. 306-318
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  • Description: Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J. Mean arterial pressure (MAP) was measured by radiotelemetry before and for 3 weeks after RD in BPH/2J and BPN/3J. The effects of pentolinium and enalaprilat were examined to determine the contribution of the SNS and RAS, respectively. After 3 weeks, MAP was −10.9 ± 2.1 mmHg lower in RD BPH/2J compared to baseline and −2.1 ± 2.2 mmHg in sham BPH/2J (P < 0.001, n = 8–10). RD had no effect in BPN/3J (P > 0.1). The depressor response to pentolinium was greater in BPH/2J than BPN/3J, but in both cases the response in RD mice was similar to sham. Enalaprilat decreased MAP more in RD BPH/2J compared to sham (−12 vs −3 mmHg, P < 0.001) but had no effect in BPN/3J. RD reduced renal noradrenaline in both strains but more so in BPH/2J. RD reduced renin mRNA and protein, but not plasma renin in BPH/2J to levels comparable with BPN/3J mice. We conclude that renal nerves contribute to hypertension in BPH mice as RD induced a sustained fall in MAP, which was associated with a reduction of intrarenal renin expression. The lack of inhibition of the depressor effects of pentolinium and enalaprilat by RD suggests that vasoconstrictor effects of the SNS or RAS are not involved.

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

  • 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.

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

  • 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.