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

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.

Enhanced Cardiac Akt/Protein Kinase B Signaling Contributes to Pathological Cardiac Hypertrophy in Part by Impairing Mitochondrial Function via Transcriptional Repression of Mitochondrion-Targeted Nuclear Genes

“…However, inducible overexpression of PGC-1␣ leads to uncontrolled mitochondrial proliferation and heart failure (44). We also reported that maintaining physiological levels of PGC-1␣ did not preserve cardiac or mitochondrial function in mice with TAC-induced LVH and heart failure (37). Thus, normalizing PGC-1␣ expression in models of pathological LVH might not counteract other molecular mechanisms that may impair mitochondrial function in the failing heart.…”

“…a metabolic pattern that mimics those associated with pathological hypertrophy. Moreover, short-term Akt activation reduced mRNA levels of Ppara and Ppargc1a, whose expression is also reduced in response to pressure overload (2,37). Thus, these changes are in contrast with the metabolic phenotype of exerciseinduced LVH (58).…”

“…7 and 10). We previously reported that in pressure overload-induced heart failure, mitochondrial dysfunction develops and expression of mitochondrial regulatory genes and nucleus-encoded FAO and OXPHOS genes was repressed (2,37,38). Although the mechanism for repression of mitochondrial function in pressure overload-induced heart failure is likely multifactorial, we sought to explore the potential contribution of long-term Akt activation.…”

Peroxisome proliferator–activated receptor gamma coactivator 1 alpha protects cardiomyocytes from hypertrophy by suppressing calcineurin-nuclear factor of activated T cells c4 signaling pathway

“…It should be noted that a certain threshold of PGC-1a is required for its cardiac protective effect, as implied by the observations that PGC-1a knockout mice accelerate cardiac dysfunction only in the late phase of pressure overload but not under baseline conditions, 24 and that sustaining physiological levels of PGC-1a expression after pressure overload hypertrophy do not prevent mitochondrial and contractile dysfunction. 36 In the heart, PGC-1a regulates most of the transcription factors involved in energy metabolism and mitochondrial biogenesis, such as peroxisome proliferator-activated receptors, nuclear respiratory factors, and …”

Insulin Signaling and Heart Failure

“…Studies of myocardial glucose uptake in subjects with heart failure need to be interpreted in light of whether or not measurements of glucose uptake were performed under basal conditions or in response to physiological or pharmacological hyperinsulinemia as would occur during a euglycemic hyperinsulinemic glucose clamp. In many animal studies in which heart failure is induced by aortic banding (thoracic or abdominal) or by coronary artery ligation, basal glucose uptake has been reported to be increased, and this has been attributable to an increase in the GLUT1 transporter 116–119 . However, when the augmentation of glucose uptake in response to insulin was evaluated, the fold increase in insulin-mediated glucose uptake was impaired relative to non-failing control groups 120 .…”