Role of Pim-1 in Smooth Muscle Cell Proliferation

The proliferation of vascular smooth muscle cells (VSMCs) and alterations of their phenotype are implicated in the pathogenesis of atherosclerosis. Arterial wall injury induces the expression of proto-oncogenes, leading to the proliferation of VSMCs. In particular, c-Myc and c-Myb play a central role in cell cycle progression and are essential for VSMC replication. The protooncogene Pim-1 cooperates with c-Myc and enhances the transcriptional activity of c-Myb in hematopoietic cells, suggesting that Pim-1 is involved in cell cycle regulation. The aim of this study was to examine the possible involvement of Pim-1 in VSMC proliferation. Pim-1 was substantially induced in neointimal VSMCs of balloon-injured rat carotid arteries, and in vivo infection with a dominant negative Pim-1-expressing adenovirus (Ad-DN-Pim-1) markedly suppressed neointima formation and cell cycle progression in the balloon-injured arteries. In cultured VSMCs, treatment with serum or H(2)O(2) induced Pim-1 expression, and H(2)O(2)- or serum-stimulated cell cycle progression and DNA synthesis were almost completely inhibited by DN-Pim-1 overexpression. Furthermore, we performed immunohisto-chemical staining for Pim-1 in human thoracic aortas and coronary arteries obtained from six individuals at autopsy and found that Pim-1-positive cells are observed predominantly in the thickened intima of the aortas and coronary arteries. To the best of our knowledge, this is the first report showing Pim-1 expression in rodent and human arterial walls. To summarize, Pim-1 expression was observed in the neointima of balloon-injured rat carotid arteries and in human thoracic aortas and coronary arteries showing intimal thickening, and the specific inhibition of Pim-1 function markedly suppressed neointima formation after balloon injury and the proliferation of cultured VSMCs, suggesting that Pim-1 plays a role in VSMC proliferation.