Antihypertensive effects of peroxisome proliferator-activated receptor-β activation in spontaneously hypertensive rats

Hypertension. 2011 Oct;58(4):733-43. doi: 10.1161/HYPERTENSIONAHA.111.174490. Epub 2011 Aug 8.

Abstract

Activation of nuclear hormone receptor peroxisome proliferator-activated receptor β/δ (PPARβ) has been shown to improve insulin resistance and plasma high-density lipoprotein levels, but nothing is known about its effects in genetic hypertension. We studied whether the PPARβ agonist GW0742 might exert antihypertensive effects in spontaneously hypertensive rats (SHRs). The rats were divided into 4 groups, Wistar Kyoto rat-control, Wistar Kyoto rat-treated (GW0742, 5 mg · kg(-1) · day(-1) by oral gavage), SHR-control, and SHR-treated, and followed for 5 weeks. GW0742 induced a progressive reduction in systolic arterial blood pressure and heart rate in SHRs and reduced the mesenteric arterial remodeling, the increased aortic vasoconstriction to angiotensin II, and the endothelial dysfunction characteristic of SHRs. These effects were accompanied by a significant increase in endothelial NO synthase activity attributed to upregulated endothelial NO synthase and downregulated caveolin 1 protein expression. Moreover, GW0742 inhibited vascular superoxide production, downregulated p22(phox) and p47(phox) proteins, decreased both basal and angiotensin II-stimulated NADPH oxidase activity, inhibited extracellular-regulated kinase 1/2 activation, and reduced the expression of the proinflammatory and proatherogenic genes, interleukin 1β, interleukin 6, or intercellular adhesion molecule 1. None of these effects were observed in Wistar Kyoto rats. PPARβ activation, both in vitro and in vivo, increased the expression of the regulators of G protein-coupled signaling proteins RGS4 and RGS5, which negatively modulated the vascular actions of angiotensin II. PPARβ activation exerted antihypertensive effects, restored the vascular structure and function, and reduced the oxidative, proinflammatory, and proatherogenic status of SHRs. We propose PPARβ as a new therapeutic target in hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Caveolin 1 / metabolism
  • Disease Models, Animal*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology
  • GTP-Binding Proteins / metabolism
  • Heart Rate / drug effects
  • Heart Rate / physiology
  • Hypertension / metabolism
  • Hypertension / physiopathology*
  • Hypertension / prevention & control*
  • Male
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • PPAR-beta / agonists
  • PPAR-beta / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Inbred SHR
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Thiazoles / pharmacology

Substances

  • Caveolin 1
  • PPAR-beta
  • Reactive Oxygen Species
  • Thiazoles
  • (4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
  • Nitric Oxide Synthase Type III
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 3
  • GTP-Binding Proteins