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

Date
2009
Authors
Zungu M.
Young M.E.
Stanley W.C.
Essop M.F.
Journal Title
Journal ISSN
Volume Title
Publisher
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. © 2009 Springer Science+Business Media, LLC.
Description
Keywords
adenosine diphosphate, cytochrome c oxidase, cytochrome c oxidase 2, phosphotransferase, pirinixic acid, pyruvate dehydrogenase, pyruvate dehydrogenase kinase 4, unclassified drug, uncoupling protein 3, animal cell, animal tissue, article, blood pressure measurement, body weight, controlled study, gene expression, heart muscle contractility, heart perfusion, heart weight, male, mitochondrial respiration, nonhuman, oxidative phosphorylation, rat, respiratory function, systolic blood pressure, upregulation, Wistar rat, Animals, Anticholesteremic Agents, Cell Respiration, Male, Mitochondria, Heart, Myocardial Contraction, Peroxisome Proliferators, PPAR alpha, Pyrimidines, Rats, Rats, Wistar, Uncoupling Agents, Rattus norvegicus
Citation
Molecular and Cellular Biochemistry
330
02-Jan