Protein kinase C-delta mediates adventitial cell migration through regulation of monocyte chemoattractant protein-1 expression in a rat angioplasty model.
OBJECTIVE
The adventitia is increasingly recognized as an important player during the development of intimal hyperplasia. However, the mechanism of adventitial cell recruitment to the subintimal space remains largely undefined. We have shown previously that gene transfer of protein kinase C-delta (PKCδ) increases apoptosis of smooth muscle cells following balloon injury. In the current study, we investigated a potential role of PKCδ in regulating the recruitment of adventitial cells.


RESULTS
Conditioned media from PKCδ-overexpressing smooth muscle cells stimulated migration and CCR2 expression of adventitial fibroblasts through a MCP-1 dependent mechanism. Following balloon injury of rat carotid arteries, overexpression of PKCδ in smooth muscle cells significantly increased MCP-1 and CCR2 expression and the number of adventitia-originated cells detected in the neointima. Administration of an anti-MCP-1 antibody markedly diminished the recruitment of adventitial cells. Combined PKCδ overexpression and anti-MCP-1 inhibited intimal hyperplasia more effectively than either approach alone.


CONCLUSIONS
Our data suggest that PKCδ regulates recruitment of adventitial cells to the neointima via a mechanism involving upregulation of the MCP-1/CCR2 signaling axis in injured arteries. Blockage of MCP-1 while enhancing apoptosis may serve as a potential therapeutic strategy to attenuate intimal hyperplasia.
Division of Vascular Surgery, University of Wisconsin Madison, 53705, USA.
Yi
Y
Si
Jun
J
Ren
Pu
P
Wang
Debra L
DL
Rateri
Alan
A
Daugherty
Xu-Dong
XD
Shi
K Craig
KC
Kent
Bo
B
Liu
D000800:Angioplasty, Balloon; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D017209:Apoptosis; D020212:Carotid Artery Injuries / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D003238:Connective Tissue / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D017077:Culture Media, Conditioned / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D015316:Genetic Therapy; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D000906:Antibodies; C491766:Ccl2 protein, rat; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D054390:Receptors, CCR2; D051745:Protein Kinase C-delta