PPARγ agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation
| Autor: | Angeles Fernandez-Gonzalez, Paul Borchert, Lavinia Maegel, Ekaterina Legchenko, Martin Meier, Philippe Chouvarine, Eva A. Rog-Zielinska, Stella Kourembanas, Georg Hansmann, Danny Jonigk, S. Alex Mitsialis, Erin Snay |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Hypertension Pulmonary Ventricular Dysfunction Right 030204 cardiovascular system & hematology 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Humans Intramyocellular lipids Heart Failure Pioglitazone business.industry Fatty Acids Hemodynamics Lipid metabolism General Medicine Hypoxia (medical) medicine.disease Pulmonary hypertension PPAR gamma 030104 developmental biology MRNA Sequencing Endocrinology Lipotoxicity Heart failure Female medicine.symptom business Oxidation-Reduction medicine.drug |
| Zdroj: | Science Translational Medicine. 10 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aao0303 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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