title: Reduction of PKCbetaII activity in smooth muscle cells attenuates acute arterial injury.
abstract: OBJECTIVE
  The ubiquitous enzyme protein kinase C (PKC) has been linked to the pathogenesis of vascular injury, but the cell-specific and discrete functions of the betaII isoform have yet to be discovered in this setting. Our previous findings demonstrated significantly increased PKCbetaII in the membrane fraction of injured femoral arteries in wild type (WT) mice and revealed reduction of neointimal expansion in PKCbeta(-/-) mice after acute vascular injury. As PKCbeta(-/-) mice are globally devoid of PKCbeta, we established novel transgenic (Tg) mice to test the hypothesis that the action of PKCbetaII specifically in smooth muscle cells (SMCs) mediates the formation of neointimal lesions in response to arterial injury.
  
  
  METHODS
  Tg mice expressing SM22alpha promoter-targeted mouse carboxyl-terminal deletion mutant PKCbetaII were produced using standard techniques, subjected to femoral artery injury and compared with littermate controls. Smooth muscle cells (SMCs) were isolated from wild type (WT) and Tg mice and exposed to a prototypic stimulus, tumor necrosis factor (TNF)-alpha. Multiple strategies were employed in vivo and in vitro to examine the molecular mechanisms underlying the specific effects of SMC PKCbetaII in neointimal expansion.
  
  
  RESULTS
  In vivo and in vitro analyses demonstrated that PKCbetaII activity in SMCs was critical for neointimal expansion in response to arterial injury, at least in part via regulation of ERK1/2, Egr-1 and induction of MMP-9.
  
  
  CONCLUSIONS
  These data identify the SMC-specific regulatory role of PKCbetaII in neointimal expansion in response to acute arterial injury, and suggest that targeted inactivation of PKCbetaII may be beneficial in limiting restenosis via suppression of the neointima-mediating effects of Egr-1 and MMP-9.
authors.affiliation: Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Huang
authors.forename: Jong Sun
authors.initials: JS
authors.lastname: Chang
authors.forename: Yunlu
authors.initials: Y
authors.lastname: Xu
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Yu Shan
authors.initials: YS
authors.lastname: Zou
authors.forename: Shi-Fang
authors.initials: SF
authors.lastname: Yan
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D015536:Down-Regulation; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000235:genetics; D042783:Endothelial Cells / Q000201:enzymology; D005263:Femoral Artery / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics; D064546:Protein Kinase C beta; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017539:Tunica Intima / Q000201:enzymology* / Q000293:injuries / Q000473:pathology
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D008840:Microfilament Proteins; D009124:Muscle Proteins; D014409:Tumor Necrosis Factor-alpha; C051615:transgelin; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse