Central role of PKCbeta in neointimal expansion triggered by acute arterial injury.
We tested the hypothesis that PKCbeta contributes to vascular smooth muscle cell (SMC) migration and proliferation; processes central to the pathogenesis of restenosis consequent to vascular injury. Homozygous PKCbeta null (-/-) mice or wild-type mice fed the PKCbeta inhibitor, ruboxistaurin, displayed significantly decreased neointimal expansion in response to acute femoral artery endothelial denudation injury compared with controls. In vivo and in vitro analyses demonstrated that PKCbetaII is critically linked to SMC activation, at least in part via regulation of ERK1/2 MAP kinase and early growth response-1. These data highlight novel roles for PKCbeta in the SMC response to acute arterial injury and suggest that blockade of PKCbeta may represent a therapeutic strategy to limit restenosis.
Andrassy
Martin
M
Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Belov
Dmitry
D
Harja
Evis
E
Zou
Yu Shan
YS
Leitges
Michael
M
Katus
Hugo A
HA
Nawroth
Peter P
PP
Yan
Shi Du
SD
Schmidt
Ann Marie
AM
Yan
Shi-Fang
SF
D000818:Animals; D001011:Aorta; D001786:Blood Glucose / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003251:Constriction, Pathologic / Q000517:prevention & control; D004268:DNA-Binding Proteins / Q000502:physiology; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D005263:Femoral Artery / Q000293:injuries* / Q000473:pathology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D053614:Janus Kinase 2; D008301:Maleimides / Q000494:pharmacology; D008698:Mesylates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D018384:Oxidative Stress; D009195:Peroxidase / Q000032:analysis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D064546:Protein Kinase C beta; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D017539:Tunica Intima / Q000201:enzymology / Q000473:pathology*
C434605:5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate; D001786:Blood Glucose; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D005419:Flavonoids; D017874:Immediate-Early Proteins; D007211:Indoles; D008301:Maleimides; D008698:Mesylates; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C099154:ruboxistaurin; D009195:Peroxidase; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one