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

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.

Phthalate Exposure Changes the Metabolic Profile of Cardiac Muscle Cells

“…Moreover, hearts overexpressing PPARα showed signs of cardiomyopathy. Treatment with the PPARα agonist Wy-14643 similarly increased PDK4 expression in both cardiac (Zungu et al 2009) and skeletal muscle (reviewed by Burri et al 2010). In comparison, PPAR α-null mice have decreased rates of FAO and increased rates of glucose oxidation (Campbell et al 2002).…”

PPARs modulate cardiac metabolism and mitochondrial function in diabetes

“…Gemfibrozil and WY-14,643 at toxicologically relevant concentrations altered mitochondrial bioenergetics through inducing the mitochondrial permeability transition which caused inhibition of oxidative phosphorylation and ATP synthesis in mitochondria in the rat liver [60]. Chronic treatment with WY-14,643 impaired myocardial contractile function while decreasing mitochondrial respiratory function and increasing mitochondrial uncoupling in rats [61]. …”

“…Chronic treatment with WY-14,643 impaired myocardial contractile function while decreasing mitochondrial respiratory function and increasing mitochondrial uncoupling in rats [61]. …”

Metabolic dysfunction in diabetic cardiomyopathy

“…Hyperglycemia also increases the levels of O-GlcNAcylated tfam, which diminish the activity of tfam and reduce the activity of oxidative phosphorylation (complex V activity). Interestingly, chronic exposure of nondiabetic rats to the PPARα agonist Wy-14,643 leads to reductions in state 3 respiration, but elevations in state 4 respiration of the heart, indicating that the rate of ADP phosphorylation is significantly depressed in Wy-14,643 treated hearts [84]. The depression in respiration in Wy-14,643 treated rats was attributed to reductions in cyclooxygenase II (COXII), a mitochondria encoded protein subunit of cytochrome oxidase.…”