Insulin stimulates endothelin-1 secretion from human endothelial cells and modulates its circulating levels in vivo.

Abstract

Endothelin-1 (ET-1) is a potent vasoactive and mitogenic peptide produced by the vascular endothelium. In this study, we evaluated whether insulin stimulates ET-1 secretion by human endothelial cells derived from umbilical cord veins and by human permanent endothelial hybrid cells Ea.hy 926. Moreover, to provide evidence that insulin may stimulate ET-1 secretion in vivo, plasma ET-1 levels were evaluated in 7 type II diabetic normotensive males (mean age, 54.3 +/- 4.0 yr) during 2-h hyperinsulinemic euglycemic clamps (287 pmol insulin/m2.min-1) as well as in 12 obese hypertensive males (mean age, 44.2 +/- 4.6 yr) before and after a 12-week period of caloric restriction. Our results showed that insulin stimulated ET-1 release from cultured endothelial cells in a dose-dependent fashion. ET-1 release persisted for 24 h and was also observed at physiological insulin concentrations (10(-9) mol/L). The insulin-induced ET-1 secretion was inhibited by genistein, a tyrosine kinase inhibitor, and by cycloheximide, a protein synthesis inhibitor, suggesting that it requires de novo protein synthesis rather than ET-1 release from intracellular stores. In the in vivo experiments, plasma ET-1 levels rapidly increased during euglycemic hyperinsulinemic clamps (from 0.76 +/- 0.18 pg/mL at time zero to 1.65 +/- 0.21 pg/mL at 60 min; P < 0.05) and persisted elevated until the end of insulin infusion (1.37 +/- 0.37 pg/mL at 120 min; P < 0.05 vs. time zero). In obese hypertensives, plasma ET-1 levels significantly decreased after 12 weeks of caloric restriction (from 0.85 +/- 0.51 to 0.48 +/- 0.28 pg/mL; P < 0.04). The decrease in body weight induced by caloric restriction was accompanied by a significant reduction in fasting insulin levels (from 167.2 +/- 94.0 to 98.9 +/- 44.9 pmol/L; P < 0.05) which correlated with the reduction in plasma ET-1 levels (r = 0.78; P < 0.003). In conclusion, our data show that insulin stimulates both in vitro and in vivo ET-1 secretion. Such interaction could play a significant role in the development of atherosclerotic lesions in hyperinsulinemic conditions.

High-Dose, Not Low-Dose Insulin Increases the Vasoconstrictor Effect of Norepinephrine in Spontaneously Hypertensive Rats: Effects of Antihypertensive Treatment

“…In a previous study, the potentiation of the vasopressin-induced vasoconstriction in mesenteric arteries of Sprague-Dawley rats was not inhibited by the selective endothelin type A receptor antagonists BQ123 [9]. In addition, in cultured endothelial cells insulin-stimulated production of endothelin-1 takes usually 2–6 h [28]. In our experimental protocol the insulin incubation time was much shorter (30 min).…”

“…It has been suggested that insulin may stimulate endothelin-1 secretion from human endothelial cells [28]. Therefore, endothelin may be responsible for insulin-induced changes in vascular contractility [29].…”

“…In our experimental protocol the insulin incubation time was much shorter (30 min). However, also very low doses of endothelin may induce an evident potentiation of vascular responses to norepinephrine, and significant increases in endothelin levels were observed after less than 60 min of stimulation with insulin both in vitro and in vivo [28]. An alternative explanation would involve an insulin-stimulated production of cyclooxygenase-dependent endothelium-derived contracting factors (such as thromboxane A 2 or prostaglandin H 2 ) [9, 37].…”

Insulin Action in the Vasculature: Physiology and Pathophysiology

“…Elevated circulating levels of ET-1 have been reported in most [55, 56, 57, 58, 59, 60, 61]but not all [62, 63]studies of human insulin resistance. The ET-1 elevation has been reported to be proportional to the hyperinsulinemia [64, 65, 66], and a dietary weight loss can reduce both serum insulin and ET-1 concentrations [67]. Furthermore, acute endogenous and exogenous elevations in circulating insulin levels in normal controls and in insulin-resistant subjects have been shown to acutely elevate circulating ET-1 [56, 68, 69], although again dissenting findings exist [70, 71, 72].…”

Endothelin-1 Stimulates Leptin Production in Adipocytes

“…On the other hand, ET-1 is known to act on adipocytes, affecting adipogenesis (57,58) and glucose metabolism (59,60). Interestingly, leptin and ET-1 production are both activated by insulin (25,61,62) and inhibited by peroxisome proliferator-activated receptor-␥ agonists (30,63), suggesting an intimate relationship among these factors.…”