Cardiovascular risk factors regulate the expression of vascular endothelin receptors

Xu, Cang‐Bao; Sun, Yang; Edvinsson, Lars

doi:10.1016/j.pharmthera.2010.04.013

Cited by 38 publications

(29 citation statements)

References 118 publications

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“…Consistent with this role of endothelins, increased EDN1 and EDNRA levels have been reported following rupture of IAs (20)(21)(22). In addition, hypertension and smoking, both well-established risk factors of IA pathogenesis, have been shown to alter the expression of endothelins (23).…”

Section: −7mentioning

confidence: 55%

Common variant near the endothelin receptor type A ( EDNRA ) gene is associated with intracranial aneurysm risk

Yasuno

Bakırcıoğlu

Low

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

102

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The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome-wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by metaanalysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5′ of the endothelin receptor type A with P = 2.2 × 10 −8 [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 × 10 −7, PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 × 10 −7, PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA.subarachnoid hemorrhage | stroke | genetic risk loci I ntracranial aneurysms (IAs) are balloon-like dilations of cerebral arteries and affect 2-5% of the population (1). Although most of these lesions are clinically silent, their rupture and consequent subarachnoid hemorrhage usually occurs between ages 40 and 60 without prior warning, resulting in substantial morbidity and mortality (2, 3).Aside from the well-established risk factors, such as hypertension, smoking, female sex (4), and high shear stress imposed on the cerebrovasculature (5), there is evidence for significant genetic contribution to IA pathogenesis (6). As is the case for other multifactorial diseases, both common and rare variants are thought to contribute to IA. In an attempt to identify common variants that confer risk of IA, we previously completed two genome-wide association studies of IA (6, 7). The larger, second genome-wide association study (7) implemented a discovery and a replication phase using samples of European and Japanese descent, respectively. Using a discovery cohort of 2,780 cases and 12,515 controls, we analyzed 831,532 genotyped and imputed autosomal SNPs for association with IA. We used a Bayesian measure of the strength of association-the posterior probability of association (PPA)-to prioritize SNPs by calculating to what extent the data supports association with IA (7). This analysis revealed five loci with PPA > 0.5. Following replication genotyping using two independent Japanese cohorts and combining the discov...

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Section: −7mentioning

confidence: 55%

Common variant near the endothelin receptor type A ( EDNRA ) gene is associated with intracranial aneurysm risk

Yasuno

Bakırcıoğlu

Low

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Interestingly, up-regulation of ETB2 receptors was also found in in vitro organ culture model of rat mesenteric arteries after long-term exposure (1-5 days) to serum-free medium (Adner et al, 1998). Recent studies demonstrated that addition of lipid-soluble cigarette smoke particles ( Huang et al, 2010 andXu et al, 2008), or lowdensity lipoprotein (Xu et al, 2010) led to increased ETB2 receptors expression and/or enhanced ETB2 receptor-mediated vasoconstriction. These in vitro findings expanded the knowledge regarding the importance of ETB2 receptor up-regulation in the development of atherosclerotic CVDs.…”

Section: Introductionmentioning

confidence: 86%

“…However, the role of ETB receptors may switch from vasodilatation (relaxing phenotype, termed ETB1) to vasoconstriction (contractile phenotype, termed ETB2) under certain pathophysiological conditions ( Stenman et al, 2002 andXu et al, 2010). The different subpopulations of ETB receptors exert distinct biological effects.…”

Section: Introductionmentioning

confidence: 99%

“…These in vitro findings expanded the knowledge regarding the importance of ETB2 receptor up-regulation in the development of atherosclerotic CVDs. The upregulated expression of ETB2 receptors resulted in potent vasoconstriction mediated by selective ETB receptor agonist sarafotoxin 6C or endogenous non-selective ETA and ETB receptor agonist ET-1, and thus modulated vascular tone and accelerated the proliferation of the VSMCs, which account for the pathogenesis of CVDs (Xu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Activation of nuclear factor-κB pathway is responsible for tumor necrosis factor-α-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro

Zhang

Zeng

et al. 2012

Toxicology Letters

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. (2012). Activation of nuclear factorkappa B pathway is responsible for tumor necrosis factor-a-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro. Toxicology Letters, 209(2), 107-112. DOI: 10.1016DOI: 10. /j.toxlet.2011 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Activation of nuclear factor-κB pathway is responsible for tumor necrosis factor-α-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro. AbstractThe endothelin B2 (ETB2) receptors are induced in vascular smooth muscle cells (VSMCs) in cardiovascular diseases. We tested if in vitro short-term exposure to the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) could up-regulate ETB2 receptors in rat mesenteric arteries, and if this effect is through activation of intracellular nuclear factor-κB (NF-κB) pathway. The mesenteric arteries were dissected from male Sprague-Dawley rats and the endothelium was removed. The arteries were co-incubated with TNF-α in serum-free Dulbecco's modified Eagle's medium. Real-time reverse transcription-PCR, Western blot and immunohistochemical staining were employed to assess the mRNA/protein expression of ETB2 receptors and activation of NF-κB pathway. The results showed that, during organ culture, TNF-α concentration-dependently enhanced ETB2 receptors expression at both mRNA and protein levels, paralleled with activation of NF-κB pathway in VSMC. The up-regulated ETB2 receptor expression and NF-κB activation could be effectively suppressed by general transcriptional inhibitor actinomycin D, or either of the selective IκB kinase inhibitors wedelolactone and IMD-0354. Conclusively, the activation of intracellular NF-κB pathway is responsible for the up-regulation of ETB2 receptors induced by short-term exposure to TNF-α. This could partly explain the toxic effects of TNF-α on VSMCs that account for cardiovascular diseases. HighlightsWe examined the mechanism of TNF-α on regulating ETB2 receptors during organ culture. TNF-α augmented ETB2 receptor expression and activated NF-κB pathway in VSMC. The inhibition of transcription or NF-κB abolished the ETB2 receptor up-regulation. NF-κB pathway is responsible for the ETB2 receptor up-regulation by TNF-α.

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“…MAPK10 and several other genes are also components of the MAPK module because the focal adhesion pathway and the MAPK signaling pathway greatly overlap. Recently, researchers have suggested that MAPK may be the key node linking cardiovascular insulin resistance, vascular endothelial dysfunction and pathogenesis of atherosclerosis (Liu and Cao, 2009;Xu et al, 2010).…”

Section: Verification By Literature Retrievalmentioning

confidence: 99%

Identification of susceptibility modules for coronary artery disease using a genome wide integrated network analysis

Duan

Luo

Chen

2013

Gene

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Cardiovascular risk factors regulate the expression of vascular endothelin receptors

Cited by 38 publications

References 118 publications

Common variant near the endothelin receptor type A ( EDNRA ) gene is associated with intracranial aneurysm risk

Common variant near the endothelin receptor type A ( EDNRA ) gene is associated with intracranial aneurysm risk

Activation of nuclear factor-κB pathway is responsible for tumor necrosis factor-α-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro

Identification of susceptibility modules for coronary artery disease using a genome wide integrated network analysis

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