PRJNA445367
Rattus norvegicus Transcriptome or Gene expression
Right ventricular (RV) failure is the leading cause of death in pulmonary arterial hypertension (PAH). PPARg acts as vasoprotective metabolic regulator in smooth muscle and endothelial cells, however, its role in the heart is unclear. We report that targeted deletion of PPARg in cardiomyocytes leads to biventricular systolic dysfunction associated with intramyocellular lipid accumulation in mice. In the SU5416/hypoxia rat model (SuHx), oral treatment with the PPARg agonist pioglitazone fully reverses severe PAH/vascular remodeling, and completely prevents RV failure. Electron microscopy identified mitochondrial disarray in failing RV cardiomyocytes, and MR spectroscopy demonstrated increased intramyocellular lipids in the SuHx heart (lipotoxicity), all of which is prevented by pioglitazone. Unbiased RV/LV miRNA-arrays, RNA-Seq., and lipid metabolism studies revealed dysregulation of cardiac hypertrophy, fibrosis, myocardial contractility, fatty acid transport/oxidation (FAO), and TGFß signaling in the failing RV; these alterations are modulated by pioglitazone through miRNA/mRNAs networks previously not known to be involved in PAH/RV dysfunction. Consistently, pre-miRs-197 and -146b greatly repressed genes that drive FAO (Cpt1b, Fabp4) in primary cardiomyocytes. Importantly, we recapitulated our major pathogenic findings in human endstage PAH: (1) in the pressure-overloaded failing RV (miR-197 and miR-146b up), (2) in peripheral pulmonary arteries (miR-146b up, miR-133b down), and (3) in plexiform vasculopathy (miR-133b up, miR-146b down), by compartment-specific analyses. Taken together, PPARg activation can normalize epigenetic and transcriptional regulation primarily related to disturbed lipid metabolism and mitochondrial morphology/function, in both the failing RV and the hypertensive pulmonary vasculature, representing a novel therapeutic approach in PAH, other cardiovascular/pulmonary diseases, and cancer.