Bcr kinase activation by angiotensin II inhibits peroxisome proliferator-activated receptor γ transcriptional activity in vascular smooth muscle cells

Jeffrey D. Alexis, Nadan Wang, Wenyi Che, Nicole Lerner-Marmarosh, Abha Sahni, Vyacheslav A. Korshunov, Yiping Zou, Bo Ding, Chen Yan, Bradford C. Berk, Jun Ichi Abe

Research output: Contribution to journalArticle

29 Citations (Scopus)

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)γ transcriptional activity was significantly decreased by Ang II. Ang II increased Bcr expression and kinase activity. Overexpression of Bcr significantly inhibited PPARγ 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 PPARγ activity significantly, suggesting the critical role of Bcr in Ang II-mediated inhibition of PPARγ activity. Point-mutation and in vitro kinase analyses showed that PPARγ was phosphorylated by Bcr at serine 82. Overexpression of wild-type Bcr kinase did not inhibit ligand-mediated PPARγ1 S82A mutant transcriptional activity, indicating that Bcr regulates PPARγ activity via S82 phosphorylation. DN-Bcr and Bcr small interfering RNA inhibited Ang II-mediated nuclear factor κB activation in VSMCs. DN-PPARγ reversed DN-Bcr-mediated inhibition of nuclear factor κB activation, suggesting that PPARγ 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 PPARγ/nuclear factor κB transcriptional activity.

Original languageEnglish (US)
Pages (from-to)69-78
Number of pages10
JournalCirculation Research
Volume104
Issue number1
DOIs
StatePublished - Jan 2 2009
Externally publishedYes

Fingerprint

Peroxisome Proliferator-Activated Receptors
Vascular Smooth Muscle
Angiotensin II
Smooth Muscle Myocytes
Phosphotransferases
Platelet-Derived Growth Factor
Small Interfering RNA
Tunica Intima
Ligands
Neointima
Protein-Serine-Threonine Kinases
Vascular System Injuries
Carotid Arteries
Point Mutation
Knockout Mice
Serine
Transcription Factors
Phosphorylation
Cell Proliferation

Keywords

  • Inflammation
  • Signal transduction
  • Smooth muscle cell

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Bcr kinase activation by angiotensin II inhibits peroxisome proliferator-activated receptor γ transcriptional activity in vascular smooth muscle cells. / Alexis, Jeffrey D.; Wang, Nadan; Che, Wenyi; Lerner-Marmarosh, Nicole; Sahni, Abha; Korshunov, Vyacheslav A.; Zou, Yiping; Ding, Bo; Yan, Chen; Berk, Bradford C.; Abe, Jun Ichi.

In: Circulation Research, Vol. 104, No. 1, 02.01.2009, p. 69-78.

Research output: Contribution to journalArticle

Alexis, Jeffrey D. ; Wang, Nadan ; Che, Wenyi ; Lerner-Marmarosh, Nicole ; Sahni, Abha ; Korshunov, Vyacheslav A. ; Zou, Yiping ; Ding, Bo ; Yan, Chen ; Berk, Bradford C. ; Abe, Jun Ichi. / Bcr kinase activation by angiotensin II inhibits peroxisome proliferator-activated receptor γ transcriptional activity in vascular smooth muscle cells. In: Circulation Research. 2009 ; Vol. 104, No. 1. pp. 69-78.
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AU - Alexis, Jeffrey D.

AU - Wang, Nadan

AU - Che, Wenyi

AU - Lerner-Marmarosh, Nicole

AU - Sahni, Abha

AU - Korshunov, Vyacheslav A.

AU - Zou, Yiping

AU - Ding, Bo

AU - Yan, Chen

AU - Berk, Bradford C.

AU - Abe, Jun Ichi

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AB - 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)γ transcriptional activity was significantly decreased by Ang II. Ang II increased Bcr expression and kinase activity. Overexpression of Bcr significantly inhibited PPARγ 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 PPARγ activity significantly, suggesting the critical role of Bcr in Ang II-mediated inhibition of PPARγ activity. Point-mutation and in vitro kinase analyses showed that PPARγ was phosphorylated by Bcr at serine 82. Overexpression of wild-type Bcr kinase did not inhibit ligand-mediated PPARγ1 S82A mutant transcriptional activity, indicating that Bcr regulates PPARγ activity via S82 phosphorylation. DN-Bcr and Bcr small interfering RNA inhibited Ang II-mediated nuclear factor κB activation in VSMCs. DN-PPARγ reversed DN-Bcr-mediated inhibition of nuclear factor κB activation, suggesting that PPARγ 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 PPARγ/nuclear factor κB transcriptional activity.

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KW - Signal transduction

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