The PPARbeta/delta agonist GW0742 relaxes pulmonary vessels and limits right heart hypertrophy in rats with hypoxia-induced pulmonary hypertension.

Abstract

BACKGROUND:

Pulmonary vascular diseases are increasingly recognised as important clinical conditions. Pulmonary hypertension associated with a range of aetiologies is difficult to treat and associated with progressive morbidity and mortality. Current therapies for pulmonary hypertension include phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, or prostacyclin mimetics. However, none of these provide a cure and the clinical benefits of these drugs individually decline over time. There is, therefore, an urgent need to identify new treatment strategies for pulmonary hypertension.

METHODOLOGY/PRINCIPAL FINDINGS:

Here we show that the PPARbeta/delta agonist GW0742 induces vasorelaxation in systemic and pulmonary vessels. Using tissue from genetically modified mice, we show that the dilator effects of GW0742 are independent of the target receptor PPARbeta/delta or cell surface prostacyclin (IP) receptors. In aortic tissue, vascular relaxant effects of GW0742 were not associated with increases in cGMP, cAMP or hyperpolarisation, but were attributed to inhibition of RhoA activity. In a rat model of hypoxia-induced pulmonary hypertension, daily oral dosing of animals with GW0742 (30 mg/kg) for 3 weeks significantly reduced the associated right heart hypertrophy and right ventricular systolic pressure. GW0742 had no effect on vascular remodelling induced by hypoxia in this model.

CONCLUSIONS/SIGNIFICANCE:

These observations are the first to show a therapeutic benefit of 'PPARbeta/delta' agonists in experimental pulmonary arterial hypertension and provide pre-clinical evidence to favour clinical trials in man.

• Authors: Louise S Harrington, Laura Moreno, Anna Reed, Stephen J Wort, Béatrice Desvergne, Christopher Garland, Lan Zhao, Jane A Mitchell
• Journal: PloS one (PLoS One) Vol. 5 Issue 3 Pg. e9526 (Mar 04 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20209098 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• PPAR delta
• PPAR-beta
• Thiazoles
• (4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
• RhoA protein, mouse
• rho GTP-Binding Proteins
• rhoA GTP-Binding Protein

Topics

• Administration, Oral
• Animals
• Cardiomegaly (drug therapy, pathology)
• Hypertension, Pulmonary (drug therapy, pathology)
• Hypoxia
• Lung (blood supply, drug effects)
• Male
• Mice
• Mice, Transgenic
• PPAR delta (agonists)
• PPAR-beta (agonists)
• Rats
• Rats, Wistar
• Thiazoles (pharmacology)
• rho GTP-Binding Proteins (metabolism)
• rhoA GTP-Binding Protein (metabolism)