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Chronic treatment with the peroxisome proliferator-activated receptor α agonist Wy-14,643 attenuates myocardial respiratory capacity and contractile function

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Abstract

We investigated whether chronic in vivo treatment with the peroxisome proliferator-activated receptor α agonist Wy-14,643 attenuates cardiac contractile function by impairing mitochondrial respiration. Wy-14,643 (25 mg kg−1 day−1) was administered to Wistar rats by oral gavage for 14 consecutive days, after which ex vivo heart function, myocardial mitochondrial respiratory capacity, and metabolic gene expression were determined. Body and heart weights were not significantly altered following 14 days of Wy-14,643 administration. Heart perfusion studies showed significantly reduced systolic and developed pressures, while the rate pressure product declined by 36 ± 2.6% (P < 0.01 vs. vehicle) after 14 days of Wy-14,643 treatment. State 3 mitochondrial respiration was lower in the Wy-14,643 group (P = 0.06 vs. vehicle). State 4 respiration and oligomycin-insensitive proton leak were significantly increased compared with matched controls. The rate of ADP phosphorylation was also decreased by 44.9 ± 1.9% (P < 0.05 vs. vehicle). Pyruvate dehydrogenase kinase 4 (PDK4) and uncoupling protein 3 (UCP3) transcript levels were upregulated, while cytochrome oxidase II (COXII) expression was decreased following Wy-14,643 treatment. This study demonstrates that chronic in vivo Wy-14,643 administration impaired cardiac contractile function in parallel with decreased mitochondrial respiratory function and increased uncoupling.

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Acknowledgments

The authors wish to thank Mr. Noel Markgraaff for his technical assistance. This work was supported by an NIH Grant No. 7 R03-TW007344-02 (to W.C. Stanley and M.F. Essop), the South African Medical Research Council and the South African National Research Foundation (to M.F. Essop).

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Authors and Affiliations

  1. Hatter Heart Research Institute, Department of Medicine, University of Cape Town Faculty of Health Sciences, Cape Town, South Africa

    Makhosazane Zungu

  2. USDA/ARS Children’s Nutrition Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Martin E. Young

  3. Division of Cardiology, Department of Medicine, University of Maryland-Baltimore, Baltimore, MD, USA

    William C. Stanley

  4. Department of Physiological Sciences, Stellenbosch University, Room 2009, Mike De Vries Building, Merriman Avenue, Stellenbosch, South Africa

    M. Faadiel Essop

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  1. Makhosazane Zungu
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Correspondence to M. Faadiel Essop.

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Zungu, M., Young, M.E., Stanley, W.C. et al. Chronic treatment with the peroxisome proliferator-activated receptor α agonist Wy-14,643 attenuates myocardial respiratory capacity and contractile function. Mol Cell Biochem 330, 55–62 (2009). https://doi.org/10.1007/s11010-009-0100-y

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