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Peroxisome proliferator-activated receptor gamma activators downregulate angiotensin II type 1 receptor in vascular

K Takeda1, T Ichiki, T Tokunou

  • 1Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Circulation
|October 12, 2000
PubMed
Abstract

Insights

Peroxisome proliferator-activated receptor gamma (PPARgamma) activators reduce Angiotensin II type 1 receptor (AT(1)-R) expression in vascular smooth muscle cells. This downregulation may explain how PPARgamma activators inhibit neointimal formation.

Area of Science:

  • Vascular Biology
  • Pharmacology
  • Molecular Medicine

Background:

  • Peroxisome proliferator-activated receptor gamma (PPARgamma) activators, like troglitazone, improve insulin resistance and inhibit neointimal formation.
  • The exact mechanisms by which PPARgamma activators suppress neointimal formation are not fully understood.
  • Angiotensin II (Ang II) is implicated in atherosclerosis, hypertension, and post-angioplasty neointimal proliferation.

Purpose of the Study:

  • To investigate the effect of PPARgamma activators on Angiotensin II type 1 receptor (AT(1)-R) expression in vascular smooth muscle cells (VSMCs).

Main Methods:

  • Quantification of AT(1)-R mRNA and protein levels using Northern blot and radioligand binding assays.
  • Assessment of VSMC calcium response to Ang II.
  • Luciferase assay to measure AT(1)-R promoter activity and mRNA stability.

Main Results:

  • Both natural and synthetic PPARgamma activators (15-deoxy-Delta(12,14)-prostaglandin J(2) and troglitazone) significantly reduced AT(1)-R mRNA and protein expression in VSMCs.
  • PPARgamma activators attenuated the calcium response of VSMCs to Ang II.
  • Suppression of AT(1)-R occurred at the transcriptional level, as indicated by reduced promoter activity and unaffected mRNA stability.

Conclusions:

  • PPARgamma activators effectively decrease AT(1)-R expression and the subsequent calcium response to Ang II in VSMCs.
  • The downregulation of AT(1)-R by PPARgamma activators may be a key mechanism contributing to the inhibition of neointimal formation.

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