Insulin stimulates endothelin binding and action on cultured vascular smooth muscle cells.
Hyperinsulinemia has been implicated as a separate risk factor for the development of accelerated cardiovascular disease, but the mechanism is unknown. Recently, we and several other groups have shown that insulin stimulates the production and secretion of the vasoconstrictor peptide endothelin-1 (ET-1) from vascular endothelial cells, and hyperinsulinemia results in increased plasma ET levels in vivo. However, the interactive effects of diabetes, insulin, and glucose on ET target tissues, like those on vascular smooth muscle cells (VSMC), are not well defined. In these studies, we examined the effects of the diabetic factors on ET receptors and [3H]thymidine incorporation into cultured cells prepared from control, streptozocin-diabetic, insulin-treated diabetic, and hyperinsulinemic rats. Scatchard analysis of saturation binding studies revealed a 2-fold increase in ET receptor number in normal VSMC treated in vitro with insulin, whereas glucose had no significant effect. Neither treatment affected receptor affinity. Similarly, aortic smooth muscle cells, brain capillary pericytes, and kidney afferent arteriolar smooth muscle cells from rats made hyperinsulinemic in vivo each showed approximately a 2-fold increase in receptor number. This increase in receptor density probably resulted from the stimulation of receptor protein production, because insulin caused a maximal 2.3 +/- 0.3 (+/- SEM) fold increase in the ETA receptor mRNA expressed in cultured VSMC by 4 h. Both insulin and ET significantly increased thymidine incorporation in aortic VSMC, but ET-1 was much more potent in this regard. However, the combined effects of insulin plus ET-1 resulted in a 10-fold increase in this index of cell proliferation, significantly different from the effects of either peptide alone. We postulate that hyperinsulinemia in vivo may potentiate ET release and receptor-mediated action, thereby contributing to vascular disease in the setting of diabetes.
Frank
H J
HJ
Department of Medicine and Pharmacology, University of California, Irvine 92717.
Levin
E R
ER
Hu
R M
RM
Pedram
A
A
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression; D007328:Insulin / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D016232:Endothelins; D007328:Insulin; D012333:RNA, Messenger; D017466:Receptors, Endothelin