TY - JOUR
T1 - Hyperglycemia inhibits vascular smooth muscle cell apoptosis through a protein kinase C-dependent pathway
AU - Hall, Jennifer L.
AU - Matter, Christian M.
AU - Wang, Xiaohong
AU - Gibbons, Gary H.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2000/9/29
Y1 - 2000/9/29
N2 - 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.
AB - 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.
KW - Blood vessel
KW - Cell death
KW - Diabetes
KW - Glucose
KW - Remodeling
KW - Vasculature
UR - http://www.scopus.com/inward/record.url?scp=0034730783&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034730783&partnerID=8YFLogxK
U2 - 10.1161/01.RES.87.7.574
DO - 10.1161/01.RES.87.7.574
M3 - Article
C2 - 11009562
AN - SCOPUS:0034730783
SN - 0009-7330
VL - 87
SP - 574
EP - 580
JO - Circulation research
JF - Circulation research
IS - 7
ER -