Protein kinase C delta mediates arterial injury responses through regulation of vascular smooth muscle cell apoptosis.
OBJECTIVE
A balance between apoptosis and proliferation of vascular smooth muscle cells (VSMC) influences the development of intimal hyperplasia. We have previously demonstrated that protein kinase C delta (PKCdelta) regulates both apoptosis and proliferation of VSMC in vitro. Here we investigate the role of PKCdelta in intimal hyperplasia through gene deletion or overexpression in rodent models of arterial injury.


RESULTS
Arterial injury was induced in mice and rats by means of carotid ligation or balloon angioplasty, respectively. Overexpression of PKCdelta was achieved by adenovirus-mediated gene transfer immediately after balloon injury in rat carotid arteries. Levels of PKCdelta protein were profoundly increased in the carotid wall 3-7 days after balloon injury, co-localizing to TUNEL-positive medial cells. When subjected to arterial injury, PKCdelta gene-deficient mice responded with an enhanced intimal hyperplasia accompanied by an 80% reduction in the number of TUNEL-positive cells detected in the injured arteries as compared with their wild-type littermates. Conversely, arterial gene transfer of PKCdelta further increased the arterial expression of PKCdelta, which was associated with a marked increase in apoptosis and reduction of intimal hyperplasia. Neither manipulation led to significant alteration in cell proliferation, suggesting that the function of PKCdelta after arterial injury is predominantly pro-apoptotic. This notion is further supported by our observation of high PKCdelta expression in human restenotic lesions that also co-localized with apoptosis.


CONCLUSIONS
The expression of PKCdelta is upregulated in the arterial wall in response to injury. This induction appears to be a mechanism of arterial response that negatively influences the degree of intimal hyperplasia by stimulating VSMC apoptosis.
Yamanouchi
Dai
D
Division of Peripheral Vascular Surgery, Department of Surgery, University of Wisconsin Madison, 1111 Highland Avenue, WIMR 5120, Madison, WI 53705, USA.
Kato
Kaori
K
Ryer
Evan J
EJ
Zhang
Fan
F
Liu
Bo
B
D000800:Angioplasty, Balloon; D000818:Animals; D017209:Apoptosis; D020212:Carotid Artery Injuries / Q000201:enzymology / Q000473:pathology*; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D051745:Protein Kinase C-delta / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000473:pathology
D051745:Protein Kinase C-delta