Insulin Stimulates Production and Secretion of Endothelin From Bovine Endothelial Cells

Abstract

Endothelin, a vasoconstrictor peptide secreted from endothelial cells, has been thought to play a role in various forms of vascular disease. Diabetes mellitus is well known for its association with accelerated atherosclerosis and microvascular damage. Although the basis for the vessel insult is multifactorial, hyperinsulinemia is thought to contribute by an unknown mechanism. In this study, we sought to determine whether insulin stimulates the production and secretion of ET-1 as a possible basis for the association of hyperinsulinemia and vascular disease. We demonstrated that insulin significantly stimulates the gene expression and secretion of ET-1 from cultured BAEC, and that insulin increases ET-1 mRNA expressed in BBCEC. Insulin caused a maximal twofold inducement above control ET-1 mRNA expression in a dose-related fashion in BAEC. The increased mRNA resulted from increased transcription, as determined by nuclear run-off studies. Increased ET-1 mRNA was seen after 4 h of incubation with insulin: the peak occurred at 6-8 h and persisted for 24 h. Insulin caused as much as a fourfold stimulation of ET-1 secretion from BAEC in a dose-related fashion, including a twofold increase at a physiological concentration (10(-9) M): The increase began at 1 h of incubation and continued for the entire 24-h incubation period. The insulin-induced increases in both ET-1 mRNA and ET-1 protein secretion were significantly attenuated by genistein, a tyrosine kinase inhibitor. This stimulation probably occurred through the insulin receptor, because IGF-1 had no effect on ET-1 gene expression or secretion from these cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Intra-islet endothelial cell and β-cell crosstalk: Implication for islet cell transplantation

“…The gene expression of ET-1 in both ECs and islet endocrine cells is regulated by hypoxia[110,111]. Insulin can also stimulate the expression and secretion of ET-1 from bovine ECs[112] and endogenous insulin can regulate circulating ET-1 concentrations in humans[113]. ET-1 also upregulates the expression of the FOXO1 gene (encoding a transcription factor) on ECs contributing to its survival[114].…”

Metabolic actions of angiotensin II and insulin: A microvascular endothelial balancing act

“…ET-1 is synthesized predominantly in vascular endothelial cells, where the endothelin gene product, preproET-1 (ppET-1) is sequentially converted to big-ET-1 (bET-1) and active ET-1 by proteases (Marasciulo et al, 2006, Khimji and Rockey, 2010). Ang II and insulin increase (Hsu, Chen, Chang et al, 2004, Hu, Levin, Pedram et al, 1993, Kobayashi, Nogami, Taguchi et al, 2008, Oliver, de la Rubia, Feener et al, 1991), while NO and PGI 2 inhibit ppET-1 expression in the endothelium (Bourque, Davidge and Adams, 2011, Prins, Hu, Nazario et al, 1994). Locally released ET-1, acting in a paracrine fashion binds to ET A receptors on VSMC causing sustained vasoconstriction (Verhaar, Strachan, Newby et al, 1998).…”

“…Although the precise transcription factors mediating insulin-stimulated expression of ET-1 are not known, an insulin-responsive element in the ET-1 gene has been identified (Oliver et al, 1991). Nevertheless, insulin exposure stimulates ET-1 secretion from the endothelium that peaks ~ 15–20 min that subsequently leads to sustained vasoconstriction (Hu et al, 1993). …”

Circulating endothelin-1 levels in obese patients with the metabolic syndrome

“…19811, NaVLi countertransport (COUNT) and Na/H antiport activities [Tedde et al 1988], vascular smooth muscle cell replication [Pfeile and Dischainet, 1981], and platelet aggregation [Hamet et al 1985], as well as by decreasing fybrinolysis [Alessi et al 19881. More recently, insulin has been suggested to promote atherogenesis by stimulating the secretion of the vasoconstrictive and mitogenic peptide endothelin-I (ET-l) [Yanagisawa et al 1988]. Indeed, a dose-dependent insulinmediated ET-1 secretion has been demonstrated from bovine [Hu et al 1993], porcine [Hattori et al 19911, and human [Fern et al l995a] endothelial cells. Accordingly, elevated plasma ET-1 levels have been found in non-insulin dependent diabetic (NIDDM) patients [Takahashi et al 1990], normotensive [Wolpert et al 19931 and hypertensive obeses [Fern et al 1995b], while insulin infusion has been reported to increase plasma ET-1 levels in NIDDM men [Hu et al 1993] [Fern et al 1995c1. To our knowledge, no studies have evaluated whether or not the metabolic syndrome is associated with increased plasma ET-1 levels.…”