TGF-β inhibits ang II-induced MAPK p44/42 signaling in vascular smooth muscle cells by Ang II type 1 receptor downregulation

Bernadet D.M. Meijering, Els A. Van Der Wouden, Vincent Pelgröm, Robert H. Henning, Kumar Sharma, Leo E. Deelman

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Vascular changes in diabetes are characterized by reduced vasoconstriction and vascular remodeling. Previously, we demonstrated that TGF-β1 impairs Ang II-induced contraction through reduced calcium mobilization. However, the effect of TGF-β1 on Ang II-induced vascular remodeling is unknown. Therefore, we investigated the effect of TGF-β1 on Ang II-induced activation of the MAPK p44/42 pathway in cultured rat aortic smooth muscle cells (RASMC). Activation of MAPK p44/42 was determined with a phospho-specific antibody. Angiotensin type 1 receptor (AT1) and AT1 mRNA levels were measured by [3H]candesartan-binding and real-time PCR, respectively. AT1 gene transcription activity was assessed using AT1 promoter-reporter constructs and by a nuclear runoff assay. In TGF-β1-pretreated cells, Ang II-induced phosphorylation of MAPK p44/42 was inhibited by 29 and 46% for p42 and p44, respectively, and AT1 density was reduced by 31%. Furthermore, pretreatment with TGF-β1 resulted in a 64% reduction in AT1 mRNA levels and decreased AT1 mRNA transcription rate by 42%. Pretreatment with TGF-β1 blocked Ang II-induced proliferation of RASMC, while stimulating Ang II-induced upregulation of plasminogen activator inhibitor-1. In conclusion, TGF-β1 attenuates Ang II-mediated MAPK p44/42 kinase signaling in RASMC through downregulation of AT1 levels, which is mainly caused by the inhibition of transcription of the AT1 gene.

Original languageEnglish (US)
Pages (from-to)459-468
Number of pages10
JournalJournal of Vascular Research
Volume46
Issue number5
DOIs
StatePublished - Aug 2009
Externally publishedYes

Keywords

  • Angiotensin II
  • ERK
  • MAPK
  • TGF-β1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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