Hyperglycemia Inhibits Vascular Smooth Muscle Cell Apoptosis Through a Protein

We hypothesized that the pathogenesis of diabetic vasculopathy involves the abnormal regulation of vascular smooth muscle cell (VSMC) apoptosis. In nondiabetic mice, a reduction in carotid artery blood flow resulted in a significant loss of medial VSMCs via apoptosis (normal flow 8461 viable VSMCs, reduced flow 7065 viable VSMCs; n512, P,0.01). In contrast, flow-induced VSMC apoptosis was markedly attenuated in streptozotocin-induced diabetic mice (normal flow 8562 viable VSMC, reduced flow 8264 viable VSMC; n513, NS). In accord with our in vivo findings, the exposure of cultured rat and human VSMCs to high glucose (17.5 mmol/L) significantly attenuated the induction of apoptosis in response to serum withdrawal (rat VSMCs in normal [5.5 mmol/L] glucose 2861%, high D-glucose 1962%; P,0.0001). High glucose also inhibited apoptosis induced by Fas ligand (100 ng/mL) (normal 2362%, high D-glucose 1362%; P,0.006). Supplementation with the nonmetabolized enantiomer L-glucose had no effect. We confirmed reports that high glucose activates protein kinase C (PKC) and demonstrated that PKC blockade with long-term phorbol ester treatment or calphostin C prevented the antiapoptotic effect (P,0.001). Moreover, the upregulation of either PKCa or PKCbII expression was sufficient to inhibit serum withdrawal–induced apoptosis (control 2562%, PKCa 1162%, PKCbII 862%; P,0.0001), whereas the upregulation of PKCd had no significant effect. Taken together, these findings demonstrate that hyperglycemia inhibits VSMC apoptosis via a PKCdependent pathway. (Circ Res. 2000;87:574-580.)