Pulmonary hypertension is a debilitating disease with no cure. We have previously shown that
peroxisome proliferator-activated receptor (
PPAR) β/δ agonists protect the right heart in
hypoxia-driven
pulmonary hypertension without affecting
vascular remodeling. PPARβ/δ 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 PPARβ 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 immunohistochemistry. 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 PPARβ/δ agonist
GW0742 has direct protective effects on the right heart in vivo. These observations identify PPARβ/δ as a viable therapeutic target to treat
pulmonary hypertension that may
complement current and future
vasodilator drugs.