The Peroxisome Proliferator–Activated Receptor β/δ Agonist GW0742 has Direct Protective Effects on Right Heart Hypertrophy

PVRI Member Authors: Akylbek Sydykov, Ralph T. Schermuly

Abstract

Pulmonary hypertension is a debilitating disease with no cure. We have previously shown that peroxisome proliferator–activated receptor (PPAR) α/α agonists protect the right heart in hypoxia-driven pulmonary hypertension without affecting vascular remodeling. PPARα/α is an important receptor in lipid metabolism, athletic performance, and the sensing of prostacyclin. Treatment of right heart hypertrophy and failure in pulmonary hypertension is an emerging target for future therapy. Here we have investigated the potential of GW0742, a PPARα agonist, to act directly on the right heart in vivo and what transcriptomic signatures are associated with its actions. Right heart hypertrophy and failure was induced in mice using a pulmonary artery banding (PAB) model. GW0742 was administered throughout the study. Cardiovascular parameters were measured using echocardiography and pressure monitoring. Fibrosis and cellular changes were measured using immuno-histochemistry. Transcriptomics were measured using the Illumina MouseRef-8v3 BeadChip array and analyzed using GeneSpring GX (ver. 11.0). PAB resulted in right heart hypertrophy and failure and in increased fibrosis. GW0742 reduced or prevented the effects of PAB on all parameters measured. GW0742 altered a number of genes in the transcriptome, with Angptl4 emerging as the top gene altered (increased) in animals with PAB. In conclusion, the PPARα/α agonist GW0742 has direct protective effects on the right heart in vivo. These observations identify PPARα/α as a viable therapeutic target to treat pulmonary hypertension that may complement current and future vasodilator drugs.

Erratum

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Topics

Heart Arrest/ Block/ Defects/ Diseases/ Failure/ Rate/ Infarction
Pulmonary Hypertension
Vasoreactivity: Vasoconstriction and Vasodilatation

Authors

Baktybek Kojonazarov, Himal Luitel, Akylbek Sydykov, Bhola K. Dahal, Mark J. Paul-Clark, Sara Bonvini, Anna Reed, Ralph T. Schermuly, Jane A. Mitchell

Published in:

Pulmonary Circulation Vol 3: No 4 cover image

December 2013

Pulmonary Circulation Vol 3: No 4

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