PPAR gamma attenuates hypoxia-induced hypertrophic transcriptional pathways in the heart

• Type of Material: Article
• Authors: Abubakr Chaudhry, Atlanta Veterans Affairs Medical Center; Kristal A. Carthan, Atlanta Veterans Affairs Medical Center; Bum-Yong Kang, Emory University; John Calvert, Emory University; Roy Sutliff, Emory University; Charles Hart, Emory University
• Language: English
• Date: 2017-01-01
• Publisher: University of Chicago Press
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2017 by Pulmonary Vascular Research Institute
• License: Creative Commons Attribution-Noncommercial 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1086/689749
• Title of Journal or Parent Work: Pulmonary Circulation
• ISSN: 2045-8932
• Volume: 7
• Issue: 1
• Start Page: 98
• End Page: 107
• Grant/Funding Information: This study was supported by funding from: Veterans Affairs Basic Laboratory Research and Development Merit Review Award (1I01BX001910 to CMH); NIH NHLBI R01 grant (HL102167 to CMH and RLS) and T32 training grant (HL076118 for KAC); and American Heart Association National Scientist Development Grant (13SDG14150004 to BYK).
• Keywords: RECEPTOR; Cardiac & Cardiovascular Systems; Life Sciences & Biomedicine; pulmonary hypertension; EXPRESSION; FAILURE; right ventricular hypertrophy; PRESSURE; Science & Technology; Cardiovascular System & Cardiology; NF-KAPPA-B; RATS; ACTIVATION; IN-VIVO; PULMONARY ARTERIAL-HYPERTENSION; nuclear factor activated T-cells (NFAT); nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B); pioglitazone; CARDIAC-HYPERTROPHY; Respiratory System
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Immunology

Abstract

Chronic hypoxia-induced pulmonary hypertension (PH) is characterized by increased pressure and resistance in the pulmonary vasculature and hypertrophy of the right ventricle (RV). The transcription factors, nuclear factor activated T-cells (NFAT), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB/p65) contribute to RV hypertrophy (RVH). Because peroxisome proliferator-activated receptor gamma (PPARγ) activation attenuates hypoxia-induced PH and RVH, we hypothesized that PPARγ inhibits activation of RV hypertrophic transcriptional signaling mechanisms. C57BL/6J mice were exposed to normoxia (21% O2) or hypoxia (10% O2) for 21 days. During the final 10 days of exposure, selected mice were treated with the PPARγ ligand, pioglitazone. RV systolic pressure (RVSP) and RVH were measured, and NFATc2 and NF-kB/p65 protein levels were measured in RV and LV nuclear and cytosolic fractions. Cardiomyocyte hypertrophy was assessed with wheatgerm agglutinin staining. NFAT activation was also examined with luciferase reporter mice and analysis of protein levels of selected transcriptional targets. Chronic-hypoxia increased: (1) RVH, RVSP, and RV cardiomyocyte hypertrophy; (2) NFATc2 and NF-κB activation in RV nuclear homogenates; (3) RV and LV NFAT luciferase activity; and (4) RV protein levels of brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MyHC). Treatment with pioglitazone attenuated hypoxia-induced increases in both RV and LV NFAT luciferase activity. Chronic hypoxia caused sustained RV NFATc2 and NF-κB activation. Pioglitazone attenuated PH, RVH, cardiomyocyte hypertrophy, and activation of RV hypertrophic signaling and also attenuated LV NFAT activation. PPARγ favorably modulates signaling derangements in the heart as well as in the pulmonary vascular wall.