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.

中文翻译：

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PPARγ激动剂吡格列酮可逆转肺动脉高压并通过脂肪酸氧化防止右心衰竭。

右心室（RV）心力衰竭是肺动脉高压（PAH）的主要死亡原因。过氧化物酶体增殖物激活受体γ（PPARγ）在平滑肌和内皮细胞中起血管保护性代谢调节剂的作用。但是，它在心脏中的作用尚不清楚。我们报道，心肌细胞中PPARγ的缺失导致小鼠双室收缩功能障碍和肌内脂质蓄积。在SU5416 /低氧（SuHx）大鼠模型中，用PPARγ激动剂吡格列酮口服治疗可完全逆转严重的PAH和血管重塑，并预防RV衰竭。失败的RV心肌细胞在SuHx心脏中表现出线粒体紊乱并增加了肌内脂质（脂毒性），这被吡格列酮所阻止。无偏心室microRNA（miRNA）阵列，mRNA测序，脂质代谢研究表明，在衰竭性RV中，心脏肥大，纤维化，心肌收缩性，脂肪酸转运/氧化（FAO）和转化生长因子β信号转导异常。吡格列酮通过以前与PAH / RV功能障碍无关的miRNA / mRNA网络调节了这些表观遗传，转录和代谢变化。一致地，pre-miR-197和pre-miR-146b抑制了原代心肌细胞中驱动FAO的基因（Cpt1b和Fabp4）。我们总结了人类末期PAH的主要病原学发现：（i）压力超负荷的RV失败（miR-197和miR-146b上调），（ii）周围肺动脉（miR-146b上调） ，miR-133b下调）和（iii）丛状血管病变（miR-133b上调，miR-146b下调）。一起，