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Bcr Kinase Activation by Angiotensin II Inhibits Peroxisome Proliferator-Activated Receptor &ggr; Transcriptional Activity in Vascular Smooth Muscle Cells

Bcr is a serine/threonine kinase activated by platelet-derived growth factor that is highly expressed in the neointima after vascular injury. Here, we demonstrate that Bcr is an important mediator of angiotensin (Ang) II and platelet-derived growth factor–mediated inflammatory responses in vascular smooth muscle cells (VSMCs). Among transcription factors that might regulate Ang II–mediated inflammatory responses we found that ligand-mediated peroxisome proliferator-activated receptor (PPAR)&ggr; transcriptional activity was significantly decreased by Ang II. Ang II increased Bcr expression and kinase activity. Overexpression of Bcr significantly inhibited PPAR&ggr; activity. In contrast, knockdown of Bcr using Bcr small interfering RNA and a dominant-negative form of Bcr (DN-Bcr) reversed Ang II–mediated inhibition of PPAR&ggr; activity significantly, suggesting the critical role of Bcr in Ang II–mediated inhibition of PPAR&ggr; activity. Point-mutation and in vitro kinase analyses showed that PPAR&ggr; was phosphorylated by Bcr at serine 82. Overexpression of wild-type Bcr kinase did not inhibit ligand-mediated PPAR&ggr;1 S82A mutant transcriptional activity, indicating that Bcr regulates PPAR&ggr; activity via S82 phosphorylation. DN-Bcr and Bcr small interfering RNA inhibited Ang II–mediated nuclear factor &kgr;B activation in VSMCs. DN-PPAR&ggr; reversed DN-Bcr–mediated inhibition of nuclear factor &kgr;B activation, suggesting that PPAR&ggr; is downstream from Bcr. Intimal proliferation in low-flow carotid arteries was decreased in Bcr knockout mice compared with wild-type mice, suggesting the critical role of Bcr kinase in VSMC proliferation in vivo, at least in part, via regulating PPAR&ggr;/nuclear factor &kgr;B transcriptional activity.