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 PKCalpha or PKCbetaII expression was sufficient to inhibit serum withdrawal-induced apoptosis (control 25+/-2%, PKCalpha 11+/-2%, PKCbetaII 8+/-2%; P:<0. 0001), whereas the upregulation of PKCdelta had no significant effect. Taken together, these findings demonstrate that hyperglycemia inhibits VSMC apoptosis via a PKC-dependent pathway.
Hall
J L
JL
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Matter
C M
CM
Wang
X
X
Gibbons
G H
GH
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000378:metabolism; D004195:Disease Models, Animal; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000473:pathology*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation
D007527:Isoenzymes; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D005947:Glucose