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

Academic Article

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.
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    Keywords

  • heart failure, mitochondria, Adenosine Triphosphate, Animals, Aorta, Apoptosis, Capillaries, Cardiomegaly, Constriction, Fibrosis, Humans, Hypertension, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Mitochondria, Heart, Myocardial Contraction, Neovascularization, Physiologic, Oxidation-Reduction, Oxidative Phosphorylation, Palmitates, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, RNA, Messenger, Recombinant Proteins, Stroke Volume, Transcription Factors, Vascular Endothelial Growth Factor A, Ventricular Remodeling
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    Author List

  • Pereira RO; Wende AR; Crum A; Hunter D; Olsen CD; Rawlings T; Riehle C; Ward WF; Abel ED
  • Start Page

  • 3691
  • End Page

  • 3702
  • Volume

  • 28
  • Issue

  • 8