Endothelin-1-Induced Signaling Pathways in Vascular Smooth Muscle Cells

Bouallegue, Ali; Daou, Grace Bou; Srivastava, Ashok K.

doi:10.2174/157016107779317161

Cited by 135 publications

(135 citation statements)

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“…ET-1 therefore contributes to the abnormal proliferation of PASMCs in PAH. When ET-1 binds its receptor, vasoconstriction and cell proliferation results in response to activation of phospholipase-C β and the second messengers diacylglycerol and Ins(1,4,5)P 3 by activating calcium channels (18). ET-1 binding also stimulates MAPK family signaling events by first activating the small guanosine triphosphates (GTPases) Ras and Raf, leading to phosphorylation of downstream MAP kinases followed by phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (see Figure 1).…”

Section: Et-1mentioning

confidence: 99%

“…ET-1 binding also stimulates MAPK family signaling events by first activating the small guanosine triphosphates (GTPases) Ras and Raf, leading to phosphorylation of downstream MAP kinases followed by phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (see Figure 1). Phosphorylation of ERK 1/2 results in p 38 MAPK and c-Jun terminal kinase activation that promotes growth signaling and controls cell survival and differentiation (18).…”

Section: Et-1mentioning

confidence: 99%

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Molecular Mechanisms of Pulmonary Arterial Remodeling

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Sun

2014

Mol Med

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Pulmonary arterial hypertension (PAH) is characterized by a persistent elevation of pulmonary arterial pressure and pulmonary arterial remodeling with unknown etiology. Current therapeutics available for PAH are primarily directed at reducing the pulmonary blood pressure through their effects on the endothelium. It is well accepted that pulmonary arterial remodeling is primarily due to excessive pulmonary arterial smooth muscle cell (PASMC) proliferation that leads to narrowing or occlusion of the pulmonary vessels. Future effective therapeutics will be successful in reversing the vascular remodeling in the pulmonary arteries and arterioles. The purpose of this review is to provide updated information on molecular mechanisms involved in pulmonary arterial remodeling with a focus on growth factors, transcription factors, and epigenetic pathways in PASMC proliferation. In addition, this review will highlight novel therapeutic strategies for potentially reversing PASMC proliferation.

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Section: Et-1mentioning

confidence: 99%

Section: Et-1mentioning

confidence: 99%

Molecular Mechanisms of Pulmonary Arterial Remodeling

Crosswhite

Sun

2014

Mol Med

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“…This results in the activation of signaling pathways that include, phospholipase A 2 , phospholipase C and further downstream protein kinase C, calmodulin, phosphatidylinositol 3-kinase and mitogenactivated protein kinases. [6][7][8][9] Receptors for ET-1 are expressed not only in smooth muscle cells but also in adipocytes and a number of other tissues. 6,10 It has recently been shown that ET-1 is released by human subcutaneous (s.c.) adipose tissue and that its secretion is elevated in obesity.…”

Section: Introductionmentioning

confidence: 99%

Endothelin-1 stimulates human adipocyte lipolysis through the ETA receptor

et al. 2008

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Objective: Levels of the vascular peptide endothelin-1 (ET-1) are significantly elevated in obesity. Adipose tissue-derived ET-1 attenuates insulin-mediated antilipolysis in human visceral adipocytes through the activation of the ET receptor B (ET B R), thereby linking ET-1 to insulin resistance. Whether ET-1 has direct effects on lipolysis in human adipocytes is not known. Research design and subjects: Endothelin-1 receptor (ETR) mRNA expression was determined by quatitative PCR in 130 nonobese and obese subjects. ET-1 mRNA in different adipose tissue regions was also assessed. ETR protein expression was analyzed by western blotting in 37 subjects. The effect of ET-1 on lipolysis was assessed in freshly isolated adipocytes and in vitro differentiated adipocytes from human donors. Results: Freshly isolated human adipocytes incubated with different concentrations of ET-1 showed no acute effect on lipolysis. In contrast, a 24 h incubation in primary cultures of human adipocytes resulted in a significant 50% increase in lipolysis. This effect was concentration dependent and could be mimicked by an agonist of the ET A receptor but not with a selective ET B R agonist. Adipocyte differentiation was not affected by any of the agonists. In subcutaneous (s.c.) adipose tissue from 19 nonobese and 18 obese subjects, the protein expression of ET A R was significantly higher in obese subjects whereas there was no difference in ET B R expression. Interestingly, the differences in protein expression were not observed at the mRNA level as ET A R expression was similar between lean and obese subjects. Conclusion: Long-term but not acute incubation of human adipocytes with ET-1 results in a significant increase in lipolysis. This appears to be mediated through the activation of ET A R, demonstrating a yet another receptor-specific effect of ET-1. In addition, the protein expression of ET A R is increased in s.c. adipose tissue in obesity, possibly through post-transcriptional mechanisms. An increased effect of ET-1 could be a mechanism that contributes to increased basal lipolysis in human obesity.

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“…We therefore investigated whether ET-1 is released by adipose tissue and may influence the antilipolytic effect of insulin in adipocytes from the visceral (omental [OM]) and subcutaneous (SC) regions. ET-1 binds to the Gq-protein coupled receptors endothelin receptor-A (ET A R) and -B (ET B R), which both mediate signaling pathways that include phospholipase C and, further downstream, protein kinase C or calmodulin (17)(18)(19). We also investigated which ETR and intracellular signaling pathways mediate the effect of ET-1 on insulin-induced antilipolysis.…”

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confidence: 99%

Vascular Peptide Endothelin-1 Links Fat Accumulation With Alterations of Visceral Adipocyte Lipolysis

et al. 2008

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OBJECTIVE-Visceral obesity increases risk of insulin resistance and type 2 diabetes. This may partly be due to a regionspecific resistance to insulin's antilipolytic effect in visceral adipocytes. We investigated whether adipose tissue releases the vascular peptide endothelin-1 (ET-1) and whether ET-1 could account for regional differences in lipolysis.RESEARCH DESIGN AND METHODS-One group consisted of eleven obese and eleven nonobese subjects in whom ET-1 levels were compared between abdominal subcutaneous and arterialized blood samples. A second group included subjects undergoing anti-obesity surgery. Abdominal subcutaneous and visceral adipose tissues were obtained to study the effect of ET-1 on differentiated adipocytes regarding lipolysis and gene and protein expression.RESULTS-Adipose tissue had a marked net release of ET-1 in vivo, which was 2.5-fold increased in obesity. In adipocytes treated with ET-1, the antilipolytic effect of insulin was attenuated in visceral but not in subcutaneous adipocytes, which could not be explained by effects of ET-1 on adipocyte differentiation. ET-1 decreased the expression of insulin receptor, insulin receptor substrate-1 and phosphodiesterase-3B and increased the expression of endothelin receptor-B (ET B R) in visceral but not in subcutaneous adipocytes. These effects were mediated via ET B R with signals through protein kinase C and calmodulin pathways. The effect of ET-1 could be mimicked by knockdown of IRS-1. A bdominal obesity contributes to the pathogenesis of insulin resistance and, thereby, type2 diabetes (1,2). Release of free fatty acids (FFAs) from fat cells during lipolysis may be involved in the negative consequences of excess adipose tissue (3-5). This process is inhibited by insulin, which activates a signaling pathway including insulin substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), AKT, and, ultimately, the enzyme phosphodiesterase-3B (PDE3B), which breaks down cyclic AMP. There are important regional variations in the antilipolytic effect of insulin. Subcutaneous adipocytes are much more sensitive than visceral adipocytes because of a higher receptoraffinity and higher expression of IRS-1 (6 -8). Site variations in adipocyte lipolysis elevate release of FFAs from the visceral compared with the subcutaneous adipose tissue during hyperinsulinemia (e.g., postprandially). Only visceral fat is linked to the liver, and a high FFA mobilization to the liver results in hepatic insulin resistance, dyslipidemia, hyperglycemia, and hyperinsulinemia, all of which are features of type 2 diabetes (3-5). CONCLUSIONS-ET-The factors that determine the relative insulin sensitivity of various adipose tissue depots are not well understood, but local environment may contribute. Adipocytes are surrounded by stromal vascular cells, including endothelial cells, which secrete endothelin-1 (ET-1), a potent vasoconstrictor. Plasma levels of ET-1 are increased in obesity and type 2 diabetes (9 -13), although the major source of circulating ET-1 in these conditions is not ...

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Endothelin-1-Induced Signaling Pathways in Vascular Smooth Muscle Cells

Cited by 135 publications

References 89 publications

Molecular Mechanisms of Pulmonary Arterial Remodeling

Molecular Mechanisms of Pulmonary Arterial Remodeling

Endothelin-1 stimulates human adipocyte lipolysis through the ETA receptor

Vascular Peptide Endothelin-1 Links Fat Accumulation With Alterations of Visceral Adipocyte Lipolysis

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