Neural suppression of miRNA-181a in the kidney elevates renin expression and exacerbates hypertension in Schlager mice
- Authors: Jackson, Kristy , Gueguen, Cindy , Lim, Kyungjoon , Eikelis, Nina , Stevenson, Emily , Charchar, Fadi , Lambert, Gavin , Burke, Sandra , Paterson, Madeleine , Marques, Francine , Head, Geoffrey
- Date: 2020
- Type: Text , Journal article
- Relation: Hypertension Research Vol. 43, no. 11 (2020), p. 1152-1164
- Full Text: false
- Reviewed:
- Description: BPH/2J mice are a genetic model of hypertension with overactivity of the sympathetic nervous system (SNS) and renin–angiotensin system (RAS). BPH/2J display higher renal renin mRNA and low levels of its negative regulator microRNA-181a (miR-181a). We hypothesise that high renal SNS activity may reduce miR-181a expression, which contributes to elevated RAS activity and hypertension in BPH/2J. Our aim was to determine whether in vivo administration of a renal-specific miR-181a mimic or whether renal denervation could increase renal miR-181a abundance to reduce renal renin mRNA, RAS activity and hypertension in BPH/2J mice. Blood pressure (BP) in BPH/2J and normotensive BPN/3J mice was measured via radiotelemetry probes. Mice were administered miR-181a mimic or a negative control (1–25 nmol, i.v., n = 6–10) with BP measured for 48 h after each dose or they underwent renal denervation or sham surgery (n = 7–9). Injection of 5–25 nmol miR-181a mimic reduced BP in BPH/2J mice after 36–48 h (−5.3 ± 1.8, −6.1 ± 1.9 mmHg, respectively, P < 0.016). Treatment resulted in lower renal renin and inflammatory marker (TLR4) mRNA levels in BPH/2J. The mimic abolished the hypotensive effect of blocking the RAS with enalaprilat (P < 0.01). No differences between mimic or vehicle were observed in BPN/3J mice except for a higher level of renal angiotensinogen in the mimic-treated mice. Renal miR-181a levels that were lower in sham BPH/2J mice were greater following renal denervation and were thus similar to those of BPN/3J. Our findings suggest that the reduced renal miR-181a may partially contribute to the elevated BP in BPH/2J mice, through an interaction between the renal sympathetic nerves and miR-181a regulation of the RAS. © 2020, The Japanese Society of Hypertension.
- Description: This work was supported by a grant from the National Health & Medical Research Council of Australia (NHMRC, Project grant 1065714) and in part by the Victorian Government’s OIS Program. Investigators were supported by NHMRC/National Heart Foundation (NHF) Postdoctoral Fellowships (NHMRC APP1091688 to KLJ, NHMRC APP1052659 and NHF PF12M6785 and 101185 to FZM) and NHMRC Research Fellowships (APP1042492 to GWL and APP1002186 to GAH).
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
- Full Text: false
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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.
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
- Full Text: false
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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.
A multi-omics glimpse into the biology of arterial stiffness
- Authors: Eales, James , Romaine, Simon , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 34, no. 1 (2015), p. 32-35
- Full Text: false
- Reviewed:
- Description: It has long been recognized that the structure of arteries throughout the vascular tree is not uniform. Notably, the media of large proximal (central) vessels contains relatively much greater amounts of elastin and elastic lamellae than smaller, more distal (peripheral) arteries; the converse is true of vascular smooth muscle cells. Under physiological conditions, the greater elasticity of central arteries compared with more muscular peripheral arteries allows conversion of the pulsatile nature of ventricular ejection into a relatively steady flow of blood at the distal end of the arterial system, conferring protection from pulsatile energy [1,2]. Furthermore, these differences in impedance can generate partial wave reflections, which arrive in the aorta during diastole, boosting diastolic blood pressure and augmenting coronary perfusion pressure [3].
Coronary artery disease predisposing haplogroup I of the Y chromosome, aggression and sex steroids - Genetic association analysis
- Authors: Bloomer, Lisa , Nelson, Christopher , Denniff, Matthew , Christofidou, Paraskevi , Debiec, Radoslaw , Thompson, John , Zukowska-Szczechowska, Ewa , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2014
- Type: Text , Journal article
- Relation: Atherosclerosis Vol. 233, no. 1 (2014), p. 160-164
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: Objective: Amongst middle-aged men, haplogroup I is associated with approximate to 50% higher risk of coronary artery disease than other paternal lineages of Y chromosome. We hypothesised that carriers of haplogroup I had higher levels of aggression and estrogens and/or lower levels of androgens early in life and thus might be more prone to cardiovascular disease than men with other lineages of Y chromosome. Methods: We reconstructed phylogenetic tree of the Y chromosome in > 1000 young apparently healthy white men from the general population. Each Y chromosome was classified into one of 13 most common European lineages. Androgens (DHEA-S, androstenedione, total testosterone) and their metabolites (total estradiol, estrone) were measured by radioimmunoassays. Information on five dimensions of aggression (total, physical, verbal, anger and hostility) was collected using Buss and Perry questionnaire. Results: Approximately 17% men inherited haplogroup I from their fathers. Carriers of haplogroup I showed lower scores of verbal aggression than men with other haplogroups (beta = -0.72, SE = 0.29, P = 0.012) and when further compared to carriers of most common R1a lineage and other haplogroups (beta = -1.03, SE = 0.34, P = 0.003). However, these associations did not survive a correction for multiple testing. Sex steroids did not show even nominal level of association with haplogroup I. Conclusion: Our data show no overall association between haplogroup I and sex-related phenotypes in young white men. These results also suggest that the previously identified association between haplogroup I and coronary artery disease is not likely mediated by unfavourable profile of sex steroids or heightened aggression early in life. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
A novel interaction between sympathetic overactivity and aberrant regulation of renin by miR-181a in BPH/2J genetically hypertensive mice
- Authors: Jackson, Kristy , Marques, Francine , Watson, Anna , Palma-Rigo, Keisia , Nguyen-Huu, Thu-Phuc , Morris, Brian , Charchar, Fadi , Davern, Pamela , Head, Geoffrey
- Date: 2013
- Type: Text , Journal article
- Relation: Hypertension Vol. 62 , no. 4 (2013), p. 775-781
- Full Text: false
- Reviewed:
- Description: Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg i.p.) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg i.p.) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin-angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin-angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.
Genetic mechanisms of vascular and renal damage
- Authors: Marques, Francine , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2013
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 31, no. 11 (2013), p. 2128-2129
- Full Text: false
- Reviewed:
- Description: Document type (note)
- Description: C4
Leading the change: Second International Society of Hypertension New Investigators' Symposium
- Authors: Veerabhadrappa, Praveen , Charchar, Fadi , Burger, Dylan , Tomaszewski, Maciej , Carlberg, Bo
- Date: 2013
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 31, no. 2 (February 2013), p. 429-430
- Full Text: false
- Reviewed:
121 Telomere attrition is attenuated in ultra-marathon runners
- Authors: Denham, Joshua , Nankervis, Scott , Debiec, Radek , Harvey, Jack , Pascoe, Deborah , Marques, Francine , O’Brien, Brendan , Zukowska-Szczechowska, Ewa , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 30, no. e-Supplement (September 2012), p. e37
- Full Text: false
- Reviewed:
- Description: Background: Leukocyte telomere length is a marker of biological ageing and its shortening is associated with cardiovascular disease. Engagement in regular moderate-intensity physical activity is a recognised method of cardiovascular disease prevention. However, it is not clear whether repeated exposure to ultra-strenuous physical exercise is beneficial long-term and whether it may attenuate biological ageing. Methods: We compared leukocyte telomere length in context of inflammation and endothelial dysfunction between 67 male ultra-marathon runners and 67 age-, sex- and BMI-matched apparently healthy controls. Genomic DNA was extracted from peripheral blood and leukocyte telomere length was measured by quantitative polymerase chain reaction assays. Adhesion molecules (sICAM-1, sE-selectin) and inflammatory markers (IL-6, C-reactive protein) concentrations were measured in 67 ultra-marathon runners by quantitative sandwich enzyme immunoassay technique, high-sensitive immunoassay and ultra-sensitive double antibody sandwich ELISA, respectively. Results: Adjusted (for age, BMI, blood pressure and lipids) leukocyte telomere length was approximately 13.8% greater in the ultra-marathon runners than in the controls (P<0.001). This translates into approximately 32.9 years difference in age-related telomere length attrition. There was a strong negative linear correlation between sICAM-1 and leukocyte telomere length in the ultra-marathon runners (r=-0.33; P=0.007) and this association retained its statistical significance after adjustment for age, BMI, blood pressure and lipids in multiple regression (P=0.026). Conclusion: Prolonged, intense physical exercise may attenuate cellular ageing possibly through a protective effect on endothelial function.
- Description: C1
The acute effects of intense cardiorespiratory exercise on human telomerase reverse transcriptase and sirtuin 6 expression in white blood cells
- Authors: Chilton, Warrick , Marques, Francine , O'Brien, Brendan , Charchar, Fadi
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 30, no. e-Supplement (September 2012), p. e49
- Full Text: false
- Reviewed:
- Description: Background: Compelling epidemiological data demonstrates that regular physical exercise reduces cardiovascular mortality. Telomeres are specialised DNA structures located at the end of linear chromosomes where they protect them from degradation during DNA replication. Telomerase reverse transcriptase (TERT) expression is essential for telomere length maintenance. Accelerated telomere shortening is associated with increased risk of cardiovascular disease (CVD). Sirtuin 6 (SIRT6) is associated with increased longevity and protection against cardiac hypertrophy. Importantly, SIRT6 maintains genomic stability by specifically associating with telomeric chromatin. We hypothesized that acute cardiorespiratory exercise will affect the immediate expression of TERT and SIRT6. Methods: Twenty four healthy adults (19-39 years old) undertook 30 minutes of continuous treadmill running at 80% of maximal oxygen uptake (VO2max). Blood samples were taken before and immediately after exercise. Total RNA was extracted from white blood cells using TRIzol(R) LS reagent. TERT and SIRT6 mRNA expression were measured by real-time PCR. Results: There was no difference in TERT (P = 0.13) and SIRT6 (P = 0.73) mRNA levels immediately after acute cardiorespiratory exercise. Resting TERT levels, however, were negatively correlated with body mass index (BMI) (P = 0.03), waist to hip ratio (P = 0.01) and diastolic blood pressure (BP) (P = 0.05), while a marginal negative correlation was observed with systolic BP (P = 0.07). Conclusions: The results indicate that intense cardiorespiratory exercise does not result in acute modulation of TERT and SIRT6 mRNA. The negative correlations between BP, BMI, waist to hip ratio and TERT levels may provide a mechanistic insight into the established negative correlations between telomere length, hypertension and obesity.
- Description: C1
Association between lipid profile and circulating concentrations of estrogens in young men
- Authors: Tomaszewski, Maciej , Maric, Christine , Zuzniewicz, Roman , Gola, Mateusz , Grzeszczak, Wladyslaw , Samani, Nilesh , Zukowska-Szczechowska, Ewa , Charchar, Fadi
- Date: 2009
- Type: Text , Journal article
- Relation: Atheroclerosis Vol. 203, no. (2009), p. 257-262
- Full Text: false
- Reviewed:
- Description: Objectives: Men show higher rates of cardiovascular morbidity and mortality than pre-menopausal women and this sexual dimorphism may be related to sex-specific effects of sex steroids on cardiovascular risk factors. Unlike androgens, estrogens were not extensively investigated in relation to cardiovascular phenotypes in men.
- Description: C1