title: Bcr kinase activation by angiotensin II inhibits peroxisome-proliferator-activated receptor gamma transcriptional activity in vascular smooth muscle cells.
abstract: 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 PPARgamma 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 PPARgamma activity significantly, suggesting the critical role of Bcr in Ang II-mediated inhibition of PPARgamma activity. Point-mutation and in vitro kinase analyses showed that PPARgamma was phosphorylated by Bcr at serine 82. Overexpression of wild-type Bcr kinase did not inhibit ligand-mediated PPARgamma1 S82A mutant transcriptional activity, indicating that Bcr regulates PPARgamma activity via S82 phosphorylation. DN-Bcr and Bcr small interfering RNA inhibited Ang II-mediated nuclear factor kappaB activation in VSMCs. DN-PPARgamma reversed DN-Bcr-mediated inhibition of nuclear factor kappaB activation, suggesting that PPARgamma 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 PPARgamma/nuclear factor kappaB transcriptional activity.
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY 14642, USA. jeffrey_alexis@urmc.rochester.edu
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Alexis
authors.forename: Nadan
authors.initials: N
authors.lastname: Wang
authors.forename: Wenyi
authors.initials: W
authors.lastname: Che
authors.forename: Nicole
authors.initials: N
authors.lastname: Lerner-Marmarosh
authors.forename: Abha
authors.initials: A
authors.lastname: Sahni
authors.forename: Vyacheslav A
authors.initials: VA
authors.lastname: Korshunov
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zou
authors.forename: Bo
authors.initials: B
authors.lastname: Ding
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Abe
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D004789:Enzyme Activation; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D051562:Proto-Oncogene Proteins c-bcr / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017539:Tunica Intima / Q000201:enzymology / Q000473:pathology; D014657:Vasculitis / Q000503:physiopathology
chemical_list: D016328:NF-kappa B; D047495:PPAR gamma; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D000804:Angiotensin II; D010768:Phosphoserine; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr