Functional Genomics and Cardiovascular Drug Discovery

Lee, Richard T.

doi:10.1161/hc3701.097176

Cited by 26 publications

(11 citation statements)

References 42 publications

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“…Because endothelial cells can mask genes that are over- or underexpressed by SMCs and vice versa [22], we removed the endothelial cells before RNA isolation. Effective removal of the endothelium was confirmed by analyzing mRNA expression of CD31, an endothelial cell marker.…”

Section: Discussionmentioning

confidence: 99%

Transcription Profiles of Aortic Smooth Muscle Cells from Atherosclerosis-Prone and -Resistant Regions in Young Apolipoprotein E-Deficient Mice before Plaque Development

Assche

Hendrickx²,

Crauwels³

et al. 2010

J Vasc Res

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Background/Aims: Site-specific atherosclerosis is generally attributed to differential gene expression in endothelial cells. We investigated whether the transcriptome of smooth muscle cells is different between atherosclerosis-prone and atherosclerosis-resistant regions in apolipoprotein E-deficient (apoE–/–) mice before plaque development, and in C57Bl/6 mice. Methods: De-endothelialized aortas (both strains: 3 males, 3 females, age 4 months) were divided into atherosclerosis-prone (AA: ascending aorta, aortic arch and proximal 2 mm of thoracic aorta) and -resistant (CTA: central thoracic aorta, i.e. 6 mm distal from the proximal 2 mm) regions. The transcriptome of these two regions was compared using whole-genome mouse microarrays. Results: Microarray analysis revealed differential expression (>2-fold difference) of 70 and 244 genes in C57Bl/6 and apoE–/– mice. This was confirmed for 6 genes using the real-time quantitative polymerase chain reaction. Up- or downregulation in the AA was observed for 33 and 37 genes in C57Bl/6, and for 186 and 58 genes in apoE–/– mice, respectively. The 201 genes that showed exclusively differential expression in apoE–/– mice were related to atherosclerotic processes, such as cell adhesion, proliferation, differentiation, motility, cell death, lipid metabolism and immune responses. Conclusion: Our findings indicate that smooth muscle cells display an altered transcriptome at atherosclerosis-prone locations before actual lesion development.

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Section: Discussionmentioning

confidence: 99%

Transcription Profiles of Aortic Smooth Muscle Cells from Atherosclerosis-Prone and -Resistant Regions in Young Apolipoprotein E-Deficient Mice before Plaque Development

Assche

Hendrickx²,

Crauwels³

et al. 2010

J Vasc Res

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“…Steady and cyclic modes of stretch have been shown to transduce differently in the aorta, the former implicating FAK (focal adhesion kinase) and the latter free radicals derived from oxidative stress and the presence of inflammatory factors [4][5][6]. Furthermore, the transcriptional profile of mechanically induced genes in VSMCs subjected to a uniform biaxial cyclic strain has been studied widely [2,7]. Cyclic stretch is found to stimulate the expression of a number of genes, including VEGF (vascular endothelial growth factor) and PAI-I (plasminogen activator inhibitor-1), but to negatively regulate others, such as extracellular MMP-1 (matrix metalloproteinase-1) and thrombomodulin.…”

Section: Mechanotransduction Of Steady and Pulsatile Stretchmentioning

confidence: 99%

Central blood pressure and hypertension: role in cardiovascular risk assessment

Safar

Jankowski

2009

Clinical Science

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Although the differences between central and peripheral BP (blood pressure) have been known for decades, the consequences of decision-making based on peripheral rather than central BP have only recently been recognized. The influence of cyclic stretch (owing to cyclic changes in BP) on the aortic wall in atherosclerosis has been documented at every stage of its development. Apart from mediating atherosclerosis progression and plaque instability, the pulsatile component of BP is the main mechanism leading to plaque rupture and, consequently, to acute coronary syndromes and other vascular complications. The principal goal of the present review is to evaluate the role of central BP measurements, principally systolic and pulse pressure, for cardiovascular risk assessment. Recent findings suggest that the pulsatile component of BP (when represented by central pulse pressure or central pulsatility) is one of the most important factors determining event-free survival. Results of several prospective studies (using both invasive and non-invasive measurements of central BP) indicate not only an independent predictive value of central pulse pressure, but also its advantage over brachial pressure. Recent evidence suggests that some antihypertensive drugs can influence central BP more consistently when compared with peripheral BP. This is especially true for agents acting on the renin-angiotensin system. Nevertheless, large prospective studies aiming at the comparison of the predictive value of peripheral and central BP in the general population, as well as studies comparing the effectiveness of hypertension management based on peripheral compared with central BP measurements, are needed before algorithms based on central BP can be recommended for clinical practice.

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“…One strategy to define new disease pathways is through high throughput screening for expression of thousands of genes in diseased tissues or cellular models, a process sometimes called functional genomics. 3 With this approach, novel gene targets can be rapidly identified through hybridization to DNA microarrays, but additional validation of novel targets in humans is essential.…”

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confidence: 99%

Identification of Serum Soluble ST2 Receptor as a Novel Heart Failure Biomarker

et al. 2003

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Background-Using genomic technology, we previously identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes. The soluble receptor form of ST2 is secreted and detectable in human serum. This study tested the hypothesis that soluble ST2 levels in the serum of patients with severe chronic heart failure are increased in patients with neurohormonal activation. Methods and Results-Serum samples, clinical variables, and neurohormone levels from the PRAISE-2 heart failure trial (NYHA functional class III-IV; end point, mortality or transplantation) were analyzed. ST2 serum measurements were performed with ELISA on samples from 161 patients obtained at trial enrollment and from 139 of the same patients obtained 2 weeks after trial enrollment. Baseline ST2 levels were correlated with baseline B-type natriuretic peptide (BNP) levels (rϭ0.36, PϽ0.0001), baseline proatrial natriuretic peptide (ProANP) levels (rϭ0.36, PϽ0.0001), and baseline norepinephrine levels (rϭ0.39, PϽ0.0001). The change in ST2 was significant as a univariate predictor of subsequent mortality or transplantation (Pϭ0.048), as was baseline BNP (PϽ0.0001) and baseline ProANP (PϽ0.0001). In multivariate models including BNP and ProANP, the change in ST2 remained significant as a predictor of mortality or transplantation independent of BNP and ProANP. Conclusions-Serum soluble ST2 is a novel biomarker for neurohormonal activation in patients with heart failure. In patients with severe chronic NYHA class III to IV heart failure, the change in ST2 levels is an independent predictor of subsequent mortality or transplantation.

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Functional Genomics and Cardiovascular Drug Discovery

Cited by 26 publications

References 42 publications

Transcription Profiles of Aortic Smooth Muscle Cells from Atherosclerosis-Prone and -Resistant Regions in Young Apolipoprotein E-Deficient Mice before Plaque Development

Transcription Profiles of Aortic Smooth Muscle Cells from Atherosclerosis-Prone and -Resistant Regions in Young Apolipoprotein E-Deficient Mice before Plaque Development

Central blood pressure and hypertension: role in cardiovascular risk assessment

Identification of Serum Soluble ST2 Receptor as a Novel Heart Failure Biomarker

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