New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus

Pernow, John; Shemyakin, Alexey; Böhm, Felix

doi:10.1016/j.lfs.2012.03.029

Cited by 126 publications

(111 citation statements)

References 137 publications

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“…Our findings that physical activity, but not DR, increases insulin-stimulated vasorelaxation as a result of decreased insulin-mediated ET-1 activation may be significant in light of evidence indicating that excess ET-1 signaling is an important contributor to the pathogenesis of macrovascular disease (47). Exercise-induced increases in blood flow and, thus, shear stress to the artery wall is a likely mechanism by which physical activity exerts an insulin-sensitizing effect on the aorta and a decrease in ET-1 (24,44).…”

Section: Discussionmentioning

confidence: 66%

Adipose tissue and vascular phenotypic modulation by voluntary physical activity and dietary restriction in obese insulin-resistant OLETF rats

Crissey

Jenkins

Lansford

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Adipose tissue (AT)-derived cytokines are proposed to contribute to obesity-associated vascular insulin resistance. We tested the hypothesis that voluntary physical activity and diet restriction-induced maintenance of body weight would both result in decreased AT inflammation and concomitant improvements in insulin-stimulated vascular relaxation in the hyperphagic, obese Otsuka Long-Evans Tokushima fatty (OLETF) rat. Rats (aged 12 wk) were randomly assigned to sedentary (SED; n ϭ 10), wheel running (WR; n ϭ 10), or diet restriction (DR; n ϭ 10; fed 70% of SED) for 8 wk. WR and DR rats exhibited markedly lower adiposity (7.1 Ϯ 0.4 and 15.7 Ϯ 1.1% body fat, respectively) relative to SED (27 Ϯ 1.2% body fat), as well as improved blood lipid profiles and systemic markers of insulin resistance. Reduced adiposity in both WR and DR was associated with decreased AT mRNA expression of inflammatory genes (e.g., MCP-1, TNF-␣, and IL-6) and markers of immune cell infiltration (e.g., CD8, CD11c, and F4/80). The extent of these effects were most pronounced in visceral AT compared with subcutaneous and periaortic AT. Markers of inflammation in brown AT were upregulated with WR but not DR. In periaortic AT, WR-and DR-induced reductions in expression and secretion of cytokines were accompanied with a more atheroprotective gene expression profile in the adjacent aortic wall. WR, but not DR, resulted in greater insulin-stimulated relaxation in the aorta; an effect that was, in part, mediated by a decrease in insulin-induced endothelin-1 activation in WR aorta. Collectively, we show in OLETF rats that lower adiposity leads to less AT and aortic inflammation, as well as an exercise-specific improvement in insulin-stimulated vasorelaxation. calorie restriction; exercise; gene expression; inflammation; obesity MORE THAN ONE-THIRD OF AMERICANS are obese (38), and the causes underlying the obesity epidemic appear to be largely related to physical inactivity and overnutrition, a set of behaviors increasingly prevalent in our society (5-7, 11, 57). Cumulative evidence indicates that obesity is an important contributor to the development of whole body insulin resistance, Type 2 diabetes, and cardiovascular disease (21). A critical link between obesity and its associated metabolic and cardiovascular diseases is thought to be chronic low-grade systemic inflammation (21). In this regard, recent studies implicate adipose tissue (AT) as a local and systemic source of inflammatory cytokines that may be involved in the instigation of vascular insulin resistance and atherosclerosis associated with obesity (12, 13, 19, 20, 31, 33-36, 45, 46, 51, 55, 56). Indeed, excessive lipid accumulation and enlargement of adipocytes in obesity are associated with infiltration of immune cells into AT, contributing to AT inflammation and subsequent secretion of proinflammatory cytokines (52). A deeper understanding of the influence of lifestyle modifications on AT inflammation and vascular insulin resistance may lead to more effective strategies aimed at prevent...

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Section: Discussionmentioning

confidence: 66%

Adipose tissue and vascular phenotypic modulation by voluntary physical activity and dietary restriction in obese insulin-resistant OLETF rats

Crissey

Jenkins

Lansford

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…[14] Produced in excess, ET-1 triggers a series of critical events comprising inflammation, oxidative stress, fibrosis, and cellular phenotypic alterations of the vascular resident cells and infiltrated immune cells which converges to vascular dysfunction and ultimately cardiovascular diseases and downstream complications. [25,26] Thus far, the pathophysiological processes involved in the induction of ET-1 are insufficiently elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…[13] Multiple mitogenic signaling pathways [(e.g., mitogen-activated protein kinases (MAPK), Janus kinase (Jak)] and pro-inflammatory transcription factors such as nuclear factor kB (NF-kB), activator protein 1 (AP-1), and members of the signal transducer and activator of transcription (STAT) family have been implicated in the regulation of ET-1 expression. [14][15][16] However, the precise molecular pathways responsible for increased ET-1 level in diabetes are not totally deciphered.…”

Section: Introductionmentioning

confidence: 99%

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

Manea¹,

Todirita²,

Heltianu³

et al. 2013

European Heart Journal

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High glucose-induced endothelial dysfunction is partially mediated by the down-stream pathophysiological effects triggered by increased expression of endothelin-1 (ET-1). The molecular control mechanisms of ET-1 synthesis are yet to be discovered. Members of the CCAAT/enhancer-binding proteins (C/EBP) family are important regulators of key metabolic processes, cellular differentiation and proinflammatory genes. In this study, we aimed at elucidating the role of C/EBP in mediating the high glucose effect on ET-1 expression in human endothelial cells (EC). Human umbilical vein cells (EAhy926) and primary cultures of human aortic EC were exposed to high levels of glucose (16.5-25 mM). Real-time PCR, Western blot, enzyme-linked immunosorbent assay, ET-1 promoter-luciferase reporter analysis, and chromatin immunoprecipitation assays were employed to investigate ET-1 regulation. High glucose activated C/EBPa, C/EBPb, and C/EBPd in a dosedependent manner. It also promoted significant increases in ET-1 gene and peptide expression. Chemical inhibition of JNK, p38MAPK and ERK1/2 diminished significantly the high glucose-induced nuclear translocation of C/EBP and ET-1 expression. Silencing of C/EBPa, C/EBPb or C/EBPd greatly reduced the high glucose-induced upregulation of ET-1 mRNA, pre-pro-ET-1, and ET-1 secretion. The expression of various C/EBP isoforms was selectively downregulated by siRNA-mediated gene silencing. In silico analysis indicated the existence of typical C/EBP elements within human ET-1 gene promoter. Transient overexpression of C/EBPa, C/EBPb or C/EBPd upregulated the luciferase level controlled by the ET-1 gene promoter. The direct interaction of C/EBPa, C/EBPb or C/EBPd proteins with the ET-1 promoter in high glucose-exposed EC was confirmed by chromatin immunoprecipitation assay. High glucose-induced ET-1 expression is mediated through multiple mechanisms. We present evidence that members of the C/EBP proinflammatory transcription factors are important regulators of ET-1 in high glucose-exposed human endothelial cells. High glucose-induced activation of C/EBP-related signaling pathways may induce excessive ET-1 synthesis, thus promoting vasoconstriction and dysfunction of the vascular wall cells in diabetes.

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“…The physiological and pathophysiological actions of ET-1 are mediated through two receptor subtypes, ET A R and ET B R. Many lines of evidence indicate that ET-1 is of pathophysiological importance in the development of several cardiovascular diseases including pulmonary arterial hypertension (PAH) (26,27), salt-sensitive hypertension (28,29), essential hypertension (30), atherosclerosis (31), cardiac remodeling after heart failure (32), and vascular complications associated with diabetes mellitus (31). At present, ETR antagonists such as bosentan are used clinically in the treatment of PAH (26,27).…”

Section: The Physiological and Pathophysiological Role Of The Et Systmentioning

confidence: 99%

Endothelin Receptor Signaling: New Insight Into Its Regulatory Mechanisms

et al. 2013

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Abstract. The endothelin (ET) system consists of two G protein coupled-receptors (GPCRs), ET type A receptor (ET A R) and ET type B receptor (ET B R), and three endogenous ligands, ET-1, ET-2, and ET-3. Stimulation of ETRs with ET-1 induces an increase in intracellular Ca 2+ concentration that is involved in a diverse array of physiological and pathophysiological processes, including vasoconstriction, and cell proliferation. Store-operated Ca 2+ entry and receptor-operated Ca 2+ entry triggered by activation of ETRs are regulated or modulated by endoplasmic reticulum Ca 2+ sensor (stromal interaction molecule 1) and voltage-independent cation channels (transient receptor potential canonical channels and Orai1). The ET-1-induced Ca 2+ mobilization results from activation of heterotrimeric G proteins by ETRs. In contrast, GPCR biology including modulation of receptor function and trafficking is regulated by a variety of GPCR interacting proteins (GIPs) that generally interact with the C-terminal domain of GPCRs. The ETR signaling is also regulated by GIPs such as Jun activation domain-binding protein 1. This review focuses on the regulatory mechanisms of the ETR signaling with special attention to the components involved in Ca 2+ signaling and to GIPs in the signal transduction, modification, and degradation of ETRs.

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New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus

Cited by 126 publications

References 137 publications

Adipose tissue and vascular phenotypic modulation by voluntary physical activity and dietary restriction in obese insulin-resistant OLETF rats

Adipose tissue and vascular phenotypic modulation by voluntary physical activity and dietary restriction in obese insulin-resistant OLETF rats

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

Endothelin Receptor Signaling: New Insight Into Its Regulatory Mechanisms

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