TGF-beta 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 Pelgrom, Robert H. Henning, Kumar Sharma, Leo E. Deelman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

Vascular changes in diabetes are characterized by reduced vasoconstriction and vascular remodeling. Previously, we demonstrated that TGF-beta 1 impairs Ang II-induced contraction through reduced calcium mobilization. However, the effect of TGF-beta 1 on Ang II-induced vascular remodeling is unknown. Therefore, we investigated the effect of TGF-beta 1 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 (AT(1)) and AT(1) mRNA levels were measured by [(3)H] candesartan-binding and real-time PCR, respectively. AT(1) gene transcription activity was assessed using AT(1) promoter-reporter constructs and by a nuclear runoff assay. In TGF-beta 1-pretreated cells, Ang II-induced phosphorylation of MAPK p44/42 was inhibited by 29 and 46% for p42 and p44, respectively, and AT(1) density was reduced by 31%. Furthermore, pretreatment with TGF-beta 1 resulted in a 64% reduction in AT(1) mRNA levels and decreased AT(1) mRNA transcription rate by 42%. Pretreatment with TGF-beta 1 blocked Ang II-induced proliferation of RASMC, while stimulating Ang II-induced upregulation of plasminogen activator inhibitor-1. In conclusion, TGF-beta 1 attenuates Ang II-mediated MAPK p44/42 kinase signaling in RASMC through downregulation of AT(1) levels, which is mainly caused by the inhibition of transcription of the AT(1) gene. Copyright (C) 2009 S. Karger AG, Basel

Original languageEnglish
Pages (from-to)459-468
Number of pages10
JournalJournal of vascular research
Volume46
Issue number5
DOIs
Publication statusPublished - 2009
Event40th Annual Meeting of the American-Society-of-Nephrology/Annual Renal Week - , Canada
Duration: 31-Oct-20075-Nov-2007

Keywords

  • Angiotensin II
  • ERK
  • MAPK
  • TGF-beta 1
  • PLASMINOGEN-ACTIVATOR INHIBITOR-1
  • GROWTH-FACTOR-BETA
  • PROXIMAL TUBULE CELLS
  • PAI-1 GENE-EXPRESSION
  • ANGIOTENSIN-II
  • HIGH GLUCOSE
  • MECHANISM
  • KINASE
  • SMAD
  • P38

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