Effects of peroxisome proliferator-activated receptor-β activation in endothelin-dependent hypertension.

Abstract

AIMS:

We analysed the chronic effects of the peroxisome proliferator-activated receptor β/δ (PPAR-β) agonist GW0742 on the renin-independent hypertension induced by deoxycorticosterone acetate (DOCA)-salt.

METHODS AND RESULTS:

Rats were treated for 5 weeks with: control-vehicle, control-GW0742 (5 or 20 mg kg(-1) day(-1)), DOCA-vehicle, DOCA-GW0742 (5 or 20 mg kg(-1) day(-1)), DOCA-GSK0660 (1 mg kg(-1) day(-1)), and DOCA-GSK0660-GW0742. Rats receiving DOCA-vehicle showed increased systolic blood pressure, left ventricular and kidney weight indices, endothelin-1 (ET-1), and malondialdehyde plasma levels, urinary iso-PGF2α excretion, impaired endothelium-dependent relaxation to acetylcholine, and contraction to ET-1 when compared with controls. Aortic reactive oxygen species content, NADPH oxidase activity, and p47(phox), p22(phox), NOX-4, glutathione peroxidase 1, hemeoxygenase-1, and preproET-1 expression were increased, whereas catalase and regulators of G protein-coupled signalling proteins (RGS)5 expression were decreased in the DOCA-vehicle group. GW0742 prevented the development of hypertension in a dose-dependent manner but the reduction of renal and cardiac hypertrophy, systemic and vascular oxidative stress markers, and improvement of endothelial dysfunction were only observed after the higher dose. GW0742, at 20 mg kg(-1) day(-1), attenuated ET-1 contraction by increasing RGS5 expression and restored the intracellular redox balance by reducing NADPH-oxidase activity, and by increasing the antioxidant genes expression. The PPAR-β antagonist GSK0660 prevented all vascular changes induced by GW0742 but not its antihypertensive effects.

CONCLUSION:

Vascular protective effects of GW0742 operate via PPAR-β by interference with the ET-1 signalling as a result of increased expression of RGS5 and up-regulation of antioxidant genes and via PPAR-β-independent mechanisms to decrease blood pressure.

• Authors: María José Zarzuelo, Manuel Gómez-Guzmán, Rosario Jiménez, Ana María Quintela, Miguel Romero, Manuel Sánchez, Antonio Zarzuelo, Juan Tamargo, Francisco Pérez-Vizcaíno, Juan Duarte
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 99 Issue 4 Pg. 622-31 (Sep 01 2013) ISSN: 1755-3245 [Electronic] England
• PMID: 23752977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• PPAR-beta
• RGS Proteins
• Reactive Oxygen Species
• Rgs5 protein, rat
• Thiazoles
• (4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
• Desoxycorticosterone Acetate
• NADPH Oxidases

Topics

• Animals
• Blood Pressure (drug effects)
• Desoxycorticosterone Acetate
• Endothelin-1 (physiology)
• Endothelium, Vascular (physiology)
• Hypertension (etiology, physiopathology)
• NADPH Oxidases (metabolism)
• PPAR-beta (physiology)
• RGS Proteins (physiology)
• Rats
• Reactive Oxygen Species (metabolism)
• Thiazoles (pharmacology)
• Vasodilation (drug effects)