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Hyperglycemia Inhibits Vascular Smooth Muscle Cell Apoptosis Through a Protein Kinase C–Dependent Pathway

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 84±1 viable VSMCs, reduced flow 70±5 viable VSMCs; n=12, P <0.01). In contrast, flow-induced VSMC apoptosis was markedly attenuated in streptozotocin-induced diabetic mice (normal flow 85±2 viable VSMC, reduced flow 82±4 viable VSMC; n=13, 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 28±1%, high d-glucose 19±2%;P <0.0001). High glucose also inhibited apoptosis induced by Fas ligand (100 ng/mL) (normal 23±2%, high d-glucose 13±2%;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 PKC&agr; or PKC&bgr;II expression was sufficient to inhibit serum withdrawal–induced apoptosis (control 25±2%, PKC&agr; 11±2%, PKC&bgr;II 8±2%;P <0.0001), whereas the upregulation of PKC&dgr; had no significant effect. Taken together, these findings demonstrate that hyperglycemia inhibits VSMC apoptosis via a PKC-dependent pathway.