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Metallothionein Prevents High-Fat Diet–Induced Cardiac Contractile Dysfunction

Role of Peroxisome Proliferator–Activated Receptor Coactivator 1 and Mitochondrial Biogenesis

From the Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, Wyoming

Address correspondence and reprint requests to Dr. Jun Ren, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071. E-mail: jren{at}uwyo.edu

Abbreviations: EDD, end-diastolic diameter; ESD, end-systolic diameter; FFI, fura-2 fluorescence intensity; mtDNA, mitochondrial DNA; mtTFA, mitochondrial transcription factor A; NRF, nuclear respiratory factor; PGC-1, peroxisome proliferator–activated receptor coactivator-1; ROS, reactive oxygen species; Sirt, silent information regulator; TPS, time to peak shortening; TR₉₀, time to 90% relengthening

Obesity is associated with oxidative stress and mitochondrial and myocardial dysfunction, although interaction among which remains elusive. This study was designed to evaluate the impact of the free radical scavenger metallothionein on high-fat diet–induced myocardial, intracellular Ca²⁺, and mitochondrial dysfunction. FVB and metallothionein transgenic mice were fed a high- or low-fat diet for 5 months to induce obesity. Echocardiography revealed decreased fractional shortening, increased end-systolic diameter, and cardiac hypertrophy in high-fat–fed FVB mice. Cardiomyocytes from high-fat–fed FVB mice displayed enhanced reactive oxygen species (ROS) production, contractile and intracellular Ca²⁺ defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and reduced intracellular Ca²⁺ rise and clearance. Transmission microscopy noted overt mitochondrial damage with reduced mitochondrial density. Western blot analysis revealed enhanced phosphorylation of nuclear factor Foxo3a without changes in Foxo3a, Foxo1a, pFoxo1a, silent information regulator (Sirt), and Akt and pAkt in hearts of high-fat diet–fed FVB mice. The peroxisome proliferator–activated receptor coactivator-1 (PGC-1), a key regulator of mitochondrial biogenesis, was significantly depressed by high-fat diet feeding and in vitro palmitic acid treatment. RT-PCR further depicted reduced levels of the PGC-1 downstream nuclear respiratory factors 1 and 2, mitochondrial transcription factor A, and mitochondrial DNA copy number in hearts of high-fat–fed FVB mice. Intriguingly, the high-fat diet–induced alterations in ROS, myocardial contractile, and mitochondrial and cell signaling were negated by metallothionein, with the exception of pFoxo3a. These data suggest that metallothionein may protect against high-fat diet–induced cardiac dysfunction possibly associated with upregulation of PGC-1 and preservation of mitochondrial biogenesis.

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