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Large artery stiffness : genes and pathwaysAl Maskari, Raya January 2018 (has links)
Aortic stiffness underlies systolic hypertension, promotes heart failure and is associated with increased cardiovascular morbidity and mortality. It is regarded as a primary driver of left ventricular hypertrophy and aortic aneurysms and is linked to the pathogenesis of cognitive impairment, stroke and renal failure. Like most cardiovascular traits, aortic stiffness is a complex trait and is moderately heritable, yet the precise molecular mechanisms that underpin the stiffening process remain poorly defined. This study aimed to employ multiple approaches to further identify the genetic basis of aortic stiffness in a large repository of human donor aortas that had undergone ex vivo pulse wave velocity (PWV) phenotyping. The first part of this work sought to investigate the molecular basis of Loeys-Dietz type 4 syndrome in a pedigree with multiple cases of aortic aneurysms and dissections. A missense variant p.(Arg320Cys) was identified in a highly evolutionary conserved region of TGFB2. There was striking upregulation of TGFB1, TGFB2 and pSMAD2/3 on imunocytochemical straining and western blotting of the aortic tissue from the index case confirming the functional importance of the variant. This case highlighted the striking paradox of predicted loss-of-function mutations in TGFB2 causing enhanced TGFβ signalling in this emerging familial aortopathy and underscored the significance of TGFβ signalling in aortic extracellular matrix biology. The second part of this work attempted to characterise the biological basis for the susceptibility locus identified in the most recent genome wide analysis of carotid-femoral PWV. While the locus lies within the 14q32.2 gene desert, it contains regulatory elements, with the transcriptional regulator B-cell CLL/lymphoma 11B (BCL11B) and non-coding RNA DB129663 representing potential targets for these enhancers. The association of five lead SNPs from the genome-wide association studies (GWAS) meta-analysis was examined for ex vivo aortic stiffness and BCL11B and DB129663 aortic mRNA expression. Three of the five SNPs associated significantly with PWV and showed allele-specific differences in BCL11B mRNA. The risk alleles associated with lower BCL11B suggesting a protective role for BCL11B. Despite the strong association, BCL11B protein was not detected in the human aorta; however, qPCR for CD markers showed that BCL11B transcript correlated strongly with markers for activated lymphocytes. In contrast, DB129663 transcripts were detected in 55% of the samples, and of the five SNPs only one showed allele-specific differences in aortic DB129663 transcripts. No significant differences were observed in PWV between samples expressing or lack- ing DB129663, and therefore the implication of this lncRNA in aortic stiffness remains elusive. The BCL11B transcript detected in the human aorta may reflect lymphocyte infiltration, suggesting that immune mechanisms contribute to the observed association with PWV. For the final part of this work genetic associations with aortic stiffness were explored in a candidate gene-based study utilising tagging SNPs to effectively capture the genetic information from linkage disequilibrium blocks. Association analyses were performed in young, healthy ENIGMA study par- ticipants selected for high and low PWV values then validated in the remaining ENIGMA cohorts. The association of four lead SNPs was then examined for ex vivo aortic stiffness in human donor aortas. The tissue expression of these SNPs and their encoded proteins was also explored. Neither the aggrecan nor the fibulin-1 SNPs showed significant associations with ex vivo PWV in the donor aortas. The exonic aggrecan tagSNP rs2882676 displayed differential transcript abundance between homozygous allele carriers but this did not translate at the protein level. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan, reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.
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Novel genes associated with airway smooth muscle proliferation in asthmaLau, Justine Yeeman, jlau@med.usyd.edu.au January 2008 (has links)
Doctor of Philosophy (PhD) / It is well recognised that both genetic and environmental factors determine an individual’s predisposition to asthma. In recent years, the airway smooth muscle (ASM) cell has come to the attention of researchers to, not merely be a contractile cell of the airway, but one that orchestrates events affecting airway remodelling and proliferation. Experiments described in this thesis have, for the first time, examined genes that are associated with various aspects of the pathogenesis of asthma by using the candidate gene approach and a genome wide search. Genes have not only been identified to be differentially expressed in ASM cells derived from asthmatic and non-asthmatic participants, but have also been linked with a functional consequence of asthma. The three genes found to be differentially regulated between ASM cells derived from asthmatic and non-asthmatic participants were Peroxisome Proliferator-Activated Receptor- gamma (PPARγ), mimecan and fibulin-1. Expression of the anti-proliferative transcriptional factor PPARγ, found by the candidate gene approach, was elevated in ASM cells derived from asthmatic participants. Whilst elevated, the anti-proliferative effect of PPARγ was absent in ASM cells derived from asthmatic participants. By microarray analysis, mimecan, an anti-proliferative agent was identified. Mimecan levels, although not different basally in ASM cells, were upregulated by transforming growth factor β (TGFβ) only in asthmatic derived ASM cells. Silencing mimecan, by the use of specific oligonucleotides, increased proliferation of ASM cells. This suggested that by increasing mimecan expression, the proliferation of ASM cells may be halted. Fibulin-1, also found by microarray analysis and the final gene examined in this thesis, was found in elevated levels in BAL fluid, serum and ASM cells obtained from asthmatic participants. In addition, ASM cells derived from asthmatic participants, for the first time were shown to have faster wound healing rates compared with nonasthmatics. The elevated fibulin-1 levels in ASM cells derived from asthmatic participants, in the presence of TGFβ, were demonstrated to contribute to this increased wound healing. Specifically, fibulin-1 was found to affect wound healing by increasing proliferation rather than migration. The current available treatments for asthma, target the contractility and inflammatory conditions in the airway. Through this thesis, novel genes discovered to be associated with proliferation may be potential therapeutic targets to treat asthma. In particular, the fibulin-1 gene is outstandingly promising, as it was shown that silencing fibulin-1 resulted in slower wound healing rates through decreased cell proliferation, to possibly inhibit the airway remodelling observed in asthma, and furthermore, corticosteroid therapy was demonstrated not to affect to this gene.
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Exploring a marker of cardiac fibrosis and its association with soluble uPAR in a bi-ethnic South African population : the SAfrEIC study / Christine Susara du PlooyDu Plooy, Christine Susara January 2013 (has links)
Background: Fibulin-1, an extracellular matrix component and mediator in cardiac fibrosis, is expressed in cardiac valves, heart muscles and blood vessels and may contribute to different cardiovascular pathological conditions such as hypertension, aortic valve stenosis, atrial fibrillation and coronary artery disease. The most conspicuous functions of fibulin-1 include cell adhesion and cell migration within the extracellular matrix (ECM). This was found to reflect vascular dysfunction contributing to the development of fibrosis in the myocardium by means of changes in the ECM, possibly as a result of inflammation.
Inflammatory mediators such as C-reactive protein (CRP) and albumin have been investigated over the years for the role they play in the inflammatory processes. However, one inflammatory mediator, soluble urokinase-type plasminogen activator receptor (suPAR), only emerged as a potential biomarker in the development of sclerotic disease. SuPAR is a soluble bioactive form of the urokinase-type plasminogen activator receptor (uPAR) secreted by inflammatory cells such as macrophages, endothelial cells and monocytes. The most profound functions of suPAR such as cell migration and cell adhesion contribute to the development of diseases such as infection, autoimmune diseases, cancer and atherosclerosis.
Motivation and aim: This study was motivated by an awareness of the limited data on the potential link between fibulin-1 and suPAR, along with other markers of inflammation (CRP and albumin). We aimed to compare the levels of a marker of cardiac fibrosis (fibulin-1) and inflammatory mediators (suPAR, CRP and albumin) in African and Caucasian men and women. A second aim was to explore fibulin-1 and its potential association with these inflammatory markers independent of haemodynamic and metabolic risk factors in a bi-ethnic cohort from South Africa. Methodology: Data from the cross-sectional SAfrEIC study (South African study regarding the role of Sex, Age and Ethnicity on Insulin sensitivity and Cardiovascular function) were used, which initially included 756 participants. Our study population comprised 290 Africans (men: n=130; women: n=160) and 343 Caucasians (men: n=160; women: n=183). We excluded HIV-infected participants (n=115) as well as those with missing data (n=8). Traditional cardiovascular measurements together with the relevant biochemical analyses were done. T-tests and Chi-square tests were used to compare means and proportions between groups, respectively. Single and partial correlations were performed to determine the relationship of fibulin-1 with suPAR, CRP and albumin, with adjustments for age. SuPAR, CRP and albumin were divided into tertiles to explore the association with fibulin-1 levels, while adjusting for age, body mass index (BMI) and diastolic blood pressure (DBP) by using analysis of covariance (ANCOVA). Multiple regression analysis was performed to explore independent associations.
Results: Participants were divided into African and Caucasian men and women due to significant interactions of the main effects of ethnicity and gender on the association of fibulin-1 with suPAR (ethnicity: F(633)=7.29; p<0.001 and gender: F(633)=7.99; p<0.001). Fibulin-1 levels were higher in African men (p=0.010), whereas CRP was higher in African women (p<0.001) compared to their Caucasian counterparts. In both gender groups suPAR levels were higher and albumin lower in Africans compared to Caucasians (p<0.006). In single regression analyses, a positive correlation existed between fibulin-1 and suPAR in African (r=0.19; p=0.028) and Caucasian men (r=0.37; p<0.001), also in African (r=0.193; p=0.028) and Caucasian women (r=0.14; p=0.036). After adjustments were applied for age, this correlation remained in African (r=0.23; p=0.010) and Caucasian men (r=0.22; p=0.005) only. An inverse correlation was found between fibulin-1 and albumin in African men (r=-0.28; p=0.002), but not in Caucasian men (r=-0.09; p=0.245). No significant correlation was found between fibulin-1 and CRP in any group. Forward stepwise regression analysis was performed in men and the previous associations between fibulin-1 and suPAR were confirmed in African and Caucasian men; along with the inverse relationship of fibulin-1 with albumin (Adj. R2=0.217; β=–0.210; p=0.013) in African men only.
Conclusion: Fibulin-1 was positively associated with suPAR in African and Caucasian men, but not in women. We also found fibulin-1 to be negatively associated with albumin in African men only. These results are indicative of the presence of potential subclinical low-grade inflammation as depicted by suPAR within the extracellular matrix. This low-grade inflammation may contribute to the potential onset of cardiac fibrosis or vascular sclerosis among these South African men with lower albumin levels. / MSc (Physiology), North-West University, Potchefstroom Campus, 2014
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Exploring a marker of cardiac fibrosis and its association with soluble uPAR in a bi-ethnic South African population : the SAfrEIC study / Christine Susara du PlooyDu Plooy, Christine Susara January 2013 (has links)
Background: Fibulin-1, an extracellular matrix component and mediator in cardiac fibrosis, is expressed in cardiac valves, heart muscles and blood vessels and may contribute to different cardiovascular pathological conditions such as hypertension, aortic valve stenosis, atrial fibrillation and coronary artery disease. The most conspicuous functions of fibulin-1 include cell adhesion and cell migration within the extracellular matrix (ECM). This was found to reflect vascular dysfunction contributing to the development of fibrosis in the myocardium by means of changes in the ECM, possibly as a result of inflammation.
Inflammatory mediators such as C-reactive protein (CRP) and albumin have been investigated over the years for the role they play in the inflammatory processes. However, one inflammatory mediator, soluble urokinase-type plasminogen activator receptor (suPAR), only emerged as a potential biomarker in the development of sclerotic disease. SuPAR is a soluble bioactive form of the urokinase-type plasminogen activator receptor (uPAR) secreted by inflammatory cells such as macrophages, endothelial cells and monocytes. The most profound functions of suPAR such as cell migration and cell adhesion contribute to the development of diseases such as infection, autoimmune diseases, cancer and atherosclerosis.
Motivation and aim: This study was motivated by an awareness of the limited data on the potential link between fibulin-1 and suPAR, along with other markers of inflammation (CRP and albumin). We aimed to compare the levels of a marker of cardiac fibrosis (fibulin-1) and inflammatory mediators (suPAR, CRP and albumin) in African and Caucasian men and women. A second aim was to explore fibulin-1 and its potential association with these inflammatory markers independent of haemodynamic and metabolic risk factors in a bi-ethnic cohort from South Africa. Methodology: Data from the cross-sectional SAfrEIC study (South African study regarding the role of Sex, Age and Ethnicity on Insulin sensitivity and Cardiovascular function) were used, which initially included 756 participants. Our study population comprised 290 Africans (men: n=130; women: n=160) and 343 Caucasians (men: n=160; women: n=183). We excluded HIV-infected participants (n=115) as well as those with missing data (n=8). Traditional cardiovascular measurements together with the relevant biochemical analyses were done. T-tests and Chi-square tests were used to compare means and proportions between groups, respectively. Single and partial correlations were performed to determine the relationship of fibulin-1 with suPAR, CRP and albumin, with adjustments for age. SuPAR, CRP and albumin were divided into tertiles to explore the association with fibulin-1 levels, while adjusting for age, body mass index (BMI) and diastolic blood pressure (DBP) by using analysis of covariance (ANCOVA). Multiple regression analysis was performed to explore independent associations.
Results: Participants were divided into African and Caucasian men and women due to significant interactions of the main effects of ethnicity and gender on the association of fibulin-1 with suPAR (ethnicity: F(633)=7.29; p<0.001 and gender: F(633)=7.99; p<0.001). Fibulin-1 levels were higher in African men (p=0.010), whereas CRP was higher in African women (p<0.001) compared to their Caucasian counterparts. In both gender groups suPAR levels were higher and albumin lower in Africans compared to Caucasians (p<0.006). In single regression analyses, a positive correlation existed between fibulin-1 and suPAR in African (r=0.19; p=0.028) and Caucasian men (r=0.37; p<0.001), also in African (r=0.193; p=0.028) and Caucasian women (r=0.14; p=0.036). After adjustments were applied for age, this correlation remained in African (r=0.23; p=0.010) and Caucasian men (r=0.22; p=0.005) only. An inverse correlation was found between fibulin-1 and albumin in African men (r=-0.28; p=0.002), but not in Caucasian men (r=-0.09; p=0.245). No significant correlation was found between fibulin-1 and CRP in any group. Forward stepwise regression analysis was performed in men and the previous associations between fibulin-1 and suPAR were confirmed in African and Caucasian men; along with the inverse relationship of fibulin-1 with albumin (Adj. R2=0.217; β=–0.210; p=0.013) in African men only.
Conclusion: Fibulin-1 was positively associated with suPAR in African and Caucasian men, but not in women. We also found fibulin-1 to be negatively associated with albumin in African men only. These results are indicative of the presence of potential subclinical low-grade inflammation as depicted by suPAR within the extracellular matrix. This low-grade inflammation may contribute to the potential onset of cardiac fibrosis or vascular sclerosis among these South African men with lower albumin levels. / MSc (Physiology), North-West University, Potchefstroom Campus, 2014
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