Hyperglycemia inhibits vascular smooth muscle cell apoptosis through a protein kinase C-dependent pathway

Jennifer L. Hall, Christian M. Matter, Xiaohong Wang, Gary H. Gibbons

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74 Scopus citations

Abstract

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 PKCα or PKCβII expression was sufficient to inhibit serum withdrawal-induced apoptosis (control 25±2%, PKCα 11±2%, PKCβII 8±2%; P<0.0001), whereas the upregulation of PKCδ had no significant effect. Taken together, these findings demonstrate that hyperglycemia inhibits VSMC apoptosis via a PKC-dependent pathway.

Original languageEnglish (US)
Pages (from-to)574-580
Number of pages7
JournalCirculation research
Volume87
Issue number7
DOIs
StatePublished - Sep 29 2000

Keywords

  • Blood vessel
  • Cell death
  • Diabetes
  • Glucose
  • Remodeling
  • Vasculature

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