Abstract:
:We investigated whether chronic in vivo treatment with the peroxisome proliferator-activated receptor alpha 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.
journal_name
Mol Cell Biochemjournal_title
Molecular and cellular biochemistryauthors
Zungu M,Young ME,Stanley WC,Essop MFdoi
10.1007/s11010-009-0100-ysubject
Has Abstractpub_date
2009-10-01 00:00:00pages
55-62issue
1-2eissn
0300-8177issn
1573-4919journal_volume
330pub_type
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