© 2000 American Heart Association, Inc.
Cellular Biology |
Hyperglycemia Inhibits Vascular Smooth Muscle Cell Apoptosis Through a Protein Kinase C–Dependent Pathway
From the Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Dr Gary H. Gibbons, Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Dr SW, Atlanta, GA 30310-1495. E-mail ggibbons{at}msm.edu
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 PKC
or PKCßII expression was sufficient to inhibit serum
withdrawal–induced apoptosis (control 25±2%, PKC 11±2%,
PKCßII 8±2%; P<0.0001), whereas the upregulation of
PKC
had no significant effect. Taken together, these findings
demonstrate that hyperglycemia inhibits VSMC apoptosis via a
PKC-dependent pathway.
Key Words: diabetes • glucose • cell death • vasculature • remodeling • blood vessel
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