Hjl. Frank et al., INSULIN STIMULATES ENDOTHELIN BINDING AND ACTION ON CULTURED VASCULARSMOOTH-MUSCLE CELLS, Endocrinology, 133(3), 1993, pp. 1092-1097
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 insu
lin stimulates the production and secretion of the vasoconstrictor pep
tide endothelin-1 (ET-1) from vascular endothelial cells, and hyperins
ulinemia results in increased plasma ET levels in vivo. However, the i
nteractive effects of diabetes, insulin, and glucose on ET target tiss
ues, like those on vascular smooth muscle cells (VSMC), are not well d
efined. In these studies, we examined the effects of the diabetic fact
ors on ET receptors and [H-3]thymidine incorporation into cultured cel
ls prepared from control, streptozocin-diabetic, insulin-treated diabe
tic, and hyperinsulinemic rats. Scatchard analysis of saturation bindi
ng 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, aort
ic smooth muscle cells, brain capillary pericytes, and kidney afferent
arteriolar smooth muscle cells from rats made hyperinsulinemic in viv
o each showed approximately a 2-fold increase in receptor number. This
increase in receptor density probably resulted from the stimulation o
f receptor protein production, because insulin caused a maximal 2.3 +/
- 0.3 (+/-SEM) fold increase in the ET(A) receptor mRNA expressed in c
ultured VSMC by 4 h. Both insulin and ET significantly increased thymi
dine incorporation in aortic VSMC, but ET-1 was much more potent in th
is regard. However, the combined effects of insulin plus ET-1 resulted
in a 10-fold increase in this index of cell proliferation, significan
tly different from the effects of either peptide alone. We postulate t
hat hyperinsulinemia in vivo may potentiate ET release and receptor-me
diated action, thereby contributing to vascular disease in the setting
of diabetes.