Bcr Kinase Activation by Angiotensin II Inhibits Peroxisome Proliferator-Activated Receptor γ 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)gamma transcriptional activity was significantly decreased by Ang II. Ang II increased Bcr expression and kinase activity. Overexpression of Bcr significantly inhibited PPAR gamma 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 gamma activity significantly, suggesting the critical role of Bcr in Ang II-mediated inhibition of PPAR gamma activity. Point-mutation and in vitro kinase analyses showed that PPAR gamma was phosphorylated by Bcr at serine 82. Overexpression of wild-type Bcr kinase did not inhibit ligand-mediated PPAR gamma 1 S82A mutant transcriptional activity, indicating that Bcr regulates PPAR gamma activity via S82 phosphorylation. DN-Bcr and Bcr small interfering RNA inhibited Ang II-mediated nuclear factor kappa B activation in VSMCs. DN-PPAR gamma reversed DN-Bcr mediated inhibition of nuclear factor kappa B activation, suggesting that PPAR gamma 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 gamma/nuclear factor kappa B transcriptional activity. (Circ Res. 2009; 104: 69-78.)