Research ArticlePulmonary Arterial Hypertension

PPARγ agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation

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Science Translational Medicine  25 Apr 2018:
Vol. 10, Issue 438, eaao0303
DOI: 10.1126/scitranslmed.aao0303

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PPARsing the role of lipid metabolism in PAH

During pulmonary hypertension, maladaptive right ventricular hypertrophy, altered mitochondrial metabolism, and occlusive pulmonary vascular remodeling can ultimately lead to heart failure. Here, Legchenko et al. show that activation of the peroxisome proliferator–activated receptor γ (PPARγ) via pioglitazone treatment protects against heart failure in the Sugen hypoxia rat model of pulmonary arterial hypertension. The differential expression of microRNAs in lung tissue and pulmonary vessels from patients with idiopathic pulmonary arterial hypertension was mirrored in the rodent model of heart failure, and cardiac lipid metabolism, genetic, and epigenetic changes associated with PAH were reversed with pioglitazone in the rodents. These findings suggest that targeting PPARγ activation to restore fatty acid oxidation could be therapeutic for pulmonary hypertension and other diseases with altered lipid metabolism.

Abstract

Right ventricular (RV) heart failure is the leading cause of death in pulmonary arterial hypertension (PAH). Peroxisome proliferator–activated receptor γ (PPARγ) acts as a vasoprotective metabolic regulator in smooth muscle and endothelial cells; however, its role in the heart is unclear. We report that deletion of PPARγ in cardiomyocytes leads to biventricular systolic dysfunction and intramyocellular lipid accumulation in mice. In the SU5416/hypoxia (SuHx) rat model, oral treatment with the PPARγ agonist pioglitazone completely reverses severe PAH and vascular remodeling and prevents RV failure. Failing RV cardiomyocytes exhibited mitochondrial disarray and increased intramyocellular lipids (lipotoxicity) in the SuHx heart, which was prevented by pioglitazone. Unbiased ventricular microRNA (miRNA) arrays, mRNA sequencing, and lipid metabolism studies revealed dysregulation of cardiac hypertrophy, fibrosis, myocardial contractility, fatty acid transport/oxidation (FAO), and transforming growth factor–β signaling in the failing RV. These epigenetic, transcriptional, and metabolic alterations were modulated by pioglitazone through miRNA/mRNA networks previously not associated with PAH/RV dysfunction. Consistently, pre-miR-197 and pre-miR-146b repressed genes that drive FAO (Cpt1b and Fabp4) in primary cardiomyocytes. We recapitulated our major pathogenic findings in human end-stage PAH: (i) in the pressure-overloaded failing RV (miR-197 and miR-146b up-regulated), (ii) in peripheral pulmonary arteries (miR-146b up-regulated, miR-133b down-regulated), and (iii) in plexiform vasculopathy (miR-133b up-regulated, miR-146b down-regulated). Together, PPARγ activation can normalize epigenetic and transcriptional regulation primarily related to disturbed lipid metabolism and mitochondrial morphology/function in the failing RV and the hypertensive pulmonary vasculature, representing a therapeutic approach for PAH and other cardiovascular/pulmonary diseases.

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