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Maintaining PGC-1α expression following pressure overload-induced cardiac hypertrophy preserves angiogenesis but not contractile or mitochondrial function
Journal article   Open access   Peer reviewed

Maintaining PGC-1α expression following pressure overload-induced cardiac hypertrophy preserves angiogenesis but not contractile or mitochondrial function

Renata O Pereira, Adam R Wende, Ashley Crum, Douglas Hunter, Curtis D Olsen, Tenley Rawlings, Christian Riehle, Walter F Ward and E Dale Abel
The FASEB journal, Vol.28(8), pp.3691-3702
08/2014
DOI: 10.1096/fj.14-253823
PMCID: PMC4101649
PMID: 24776744
url
https://doi.org/10.1096/fj.14-253823View
Published (Version of record) Open Access

Abstract

During pathological hypertrophy, peroxisome proliferator-activated receptor coactivator 1α (PGC-1α) is repressed in concert with reduced mitochondrial oxidative capacity and fatty acid oxidation (FAO). We therefore sought to determine if maintaining or increasing PGC-1α levels in the context of pressure overload hypertrophy (POH) would preserve mitochondrial function and prevent contractile dysfunction. Pathological cardiac hypertrophy was induced using 4 wk of transverse aortic constriction (TAC) in mice overexpressing the human PGC-1α genomic locus via a bacterial artificial chromosome (TG) and nontransgenic controls (Cont). PGC-1α levels were increased by 40% in TG mice and were sustained following TAC. Although TAC-induced repression of FAO genes and oxidative phosphorylation (oxphos) genes was prevented in TG mice, mitochondrial function and ATP synthesis were equivalently impaired in Cont and TG mice after TAC. Contractile function was also equally impaired in Cont and TG mice following TAC, as demonstrated by decreased +dP/dt and ejection fraction and increased left ventricular developed pressure and end diastolic pressure. Conversely, capillary density was preserved, in concert with increased VEGF expression, while apoptosis and fibrosis were reduced in TG relative to Cont mice after TAC. Hence, sustaining physiological levels of PGC-1α expression following POH, while preserving myocardial vascularity, does not prevent mitochondrial and contractile dysfunction.
 Vascular Endothelial Growth Factor A - biosynthesis Humans Myocardial Contraction - physiology Cardiomegaly - etiology Adenosine Triphosphate - biosynthesis Vascular Endothelial Growth Factor A - genetics RNA, Messenger - biosynthesis Ventricular Remodeling Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Aorta Mice, Inbred DBA Recombinant Proteins - metabolism Transcription Factors - physiology Capillaries - ultrastructure Constriction Oxidation-Reduction Mice, Inbred C57BL Oxidative Phosphorylation Cardiomegaly - physiopathology Mice, Transgenic Transcription Factors - biosynthesis Transcription Factors - genetics Stroke Volume Neovascularization, Physiologic - physiology Animals Mitochondria, Heart - physiology Fibrosis Hypertension - complications Mice Palmitates - metabolism Apoptosis

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