Prostacyclin, Atherothrombosis, and Cardiovascular Disease

Arehart, Eric; Gleim, Scott; Kasza, Zsolt; Fetalvero, Kristina M.; Martin, Kathleen A.; Hwa, John

doi:10.2174/092986707781389637

Cited by 28 publications

(19 citation statements)

References 99 publications

(129 reference statements)

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“…It is a 20-carbon oxygenated fatty acid, derived from arachidonic acid, which acts as a vasodilator, platelet aggregation inhibitor, and VSMC proliferation inducer. 151,152 Prostacyclin acts on smooth muscle receptors to activate adenylate cyclase and inhibit vasoconstriction. 152 The PGI 2 pathway, as a vasodilatory system, has some redundancy with the NO system: PGI 2 increases endothelial cell NO production, and NO increases PGI 2 activity on smooth muscle relaxation.…”

Section: Endothelial Function and The Regulation Of Vasomotor Tonementioning

confidence: 99%

“…151,152 Prostacyclin acts on smooth muscle receptors to activate adenylate cyclase and inhibit vasoconstriction. 152 The PGI 2 pathway, as a vasodilatory system, has some redundancy with the NO system: PGI 2 increases endothelial cell NO production, and NO increases PGI 2 activity on smooth muscle relaxation. 153 In this capacity, it may function in a compensatory role when other vasorelaxation mechanisms are not functioning (for example, in eNOS-deficient mice who cannot produce NO).…”

Section: Endothelial Function and The Regulation Of Vasomotor Tonementioning

confidence: 99%

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Gender Differences in Cardiovascular Disease: Hormonal and Biochemical Influences

et al. 2010

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Objective Atherosclerosis is a complex process characterized by an increase in vascular wall thickness owing to the accumulation of cells and extracellular matrix between the endothelium and the smooth muscle cell wall. There is evidence that females are at lower risk of developing cardiovascular disease (CVD) as compared to males. This has led to an interest in examining the contribution of genetic background and sex hormones to the development of CVD. The objective of this review is to provide an overview of factors, including those related to gender, that influence CVD. Methods Evidence analysis from PubMed and individual searches concerning biochemical and endocrine influences and gender differences, which affect the origin and development of CVD. Results Although still controversial, evidence suggests that hormones including estradiol and androgens are responsible for subtle cardiovascular changes long before the development of overt atherosclerosis. Conclusion Exposure to sex hormones throughout an individual's lifespan modulates many endocrine factors involved in atherosclerosis.

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Section: Endothelial Function and The Regulation Of Vasomotor Tonementioning

confidence: 99%

Section: Endothelial Function and The Regulation Of Vasomotor Tonementioning

confidence: 99%

Gender Differences in Cardiovascular Disease: Hormonal and Biochemical Influences

et al. 2010

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“…PGI 2 is predominantly produced by endothelial cells and has potent anti-inflammatory, antiplatelet, anti-proliferative and vasodilatory effects [2]. TXA 2 is mainly produced by activated platelets where it promotes aggregation during thrombus formation.…”

Section: Introductionmentioning

confidence: 99%

Cyclic stretch induces cyclooxygenase-2 gene expression in vascular endothelial cells via activation of nuclear factor kappa-β

Zhao

Hiroi

Hansen

et al. 2009

Biochemical and Biophysical Research Communications

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Vascular endothelial cells respond to biomechanical forces, such as cyclic stretch and shear stress, by altering gene expression. Since endothelial-derived prostanoids, such as prostacyclin and thromboxane A 2 , are key mediators of endothelial function, we investigated the effects of cyclic stretch on the expression of genes in human umbilical vein endothelial cells controlling prostanoid synthesis: cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), prostacyclin synthase (PGIS) and thromboxane A 2 synthase (TXAS). COX-2 and TXAS mRNAs were upregulated by cyclic stretch for 24 hours. In contrast, PGIS mRNA was decreased and stretch had no effect on COX-1 mRNA expression. We further show that stretch-induced upregulation of COX-2 is mediated by activation of the NF-κB signaling pathway.

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“…This is particularly important and timely with recent demonstration of the critical role that hIP plays in development of cardiovascular disease (27,34,35). Characterization of these mutations additionally provides important insights into the amino acid requirements for hIP structure and function and the importance of complementing basic sciences with clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Biochemical Analysis of Rare Prostacyclin Receptor Variants

Stitham

Arehart²,

Elderon³

et al. 2011

Journal of Biological Chemistry

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Currently, pharmacogenetic studies are at an impasse as the low prevalence (<2%) of most variants hinder their pharmacogenetic analysis with population sizes often inadequate for sufficiently powered studies. Grouping rare mutations by functional phenotype rather than mutation site can potentially increase sample size. Using human population-based studies (n ‫؍‬ 1,761) to search for dysfunctional human prostacyclin receptor (hIP) variants, we recently discovered 18 non-synonymous mutations, all with frequencies less than 2% in our study cohort. Eight of the 18 had defects in binding, activation, and/or protein stability/folding. Mutations (M113T, L104R, and R279C) in three highly conserved positions demonstrated severe misfolding manifested by impaired binding and activation of cell surface receptors. To assess for association with coronary artery disease, we performed a case-control study comparing coronary angiographic results from patients with reduced cAMP production arising from the non-synonymous mutations (n ‫؍‬ 23) with patients with non-synonymous mutations that had no reduction in cAMP (n ‫؍‬ 17). Major coronary artery obstruction was significantly increased in the dysfunctional mutation group in comparison with the silent mutations. We then compared the 23 dysfunctional receptor patients with 69 age-and risk factor-matched controls (1:3). This verified the significantly increased coronary disease in the non-synonymous dysfunctional variant cohort. This study demonstrates the potential utility of in vitro functional characterization in predicting clinical phenotypes and represents the most comprehensive characterization of human prostacyclin receptor genetic variants to date. Single nucleotide polymorphisms (SNPs)3 occurring in DNA coding regions are sequence changes that result in either synonymous (i.e. no change in amino acid sequence) or non-synonymous (change in amino acid sequence) mutations. They are implicated in the pathogenesis of diseases (1), in the efficacy of drugs, and in drug-to-drug interactions (2-4). It is now generally believed that greater than 80% of the observed variability between individuals is the result of genetic variants (5). Numerous databases, including the National Center for Biotechnology Information SNP database, have accumulated millions of SNPs, and a growing list of clinical trials seeks to address the role of SNPs in pathophysiology and treatment response (6 -8). Despite the rapid accumulation of data, surprisingly little has entered clinical practice. This may be in part due to the requirement for very large cohorts to perform an adequately powered study for the rarer mutations. Detailed genetic variant functional analysis in biochemical systems may provide a possible solution.The human prostacyclin receptor gene (PTGIR) spans ϳ7,000 bases along chromosome 19 (locus 19q13.3) and comprises three exons separated by two introns: one intron lies upstream from the ATG start codon, and the other lies at the end of the sixth transmembrane helix (9). The human prostacycli...

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Prostacyclin, Atherothrombosis, and Cardiovascular Disease

Cited by 28 publications

References 99 publications

Gender Differences in Cardiovascular Disease: Hormonal and Biochemical Influences

Gender Differences in Cardiovascular Disease: Hormonal and Biochemical Influences

Cyclic stretch induces cyclooxygenase-2 gene expression in vascular endothelial cells via activation of nuclear factor kappa-β

Comprehensive Biochemical Analysis of Rare Prostacyclin Receptor Variants

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