WY14643 improves left ventricular myocardial mitochondrial and systolic functions in obese rats under chronic persistent hypoxia via the PPARα pathway.

Aims: Peroxisome proliferator-activated receptor (PPAR) α, a key regulator of lipid metabolism, plays a role in maintaining the homeostasis of myocardial energy metabolism. Both hypoxia and obesity inhibit the expression of PPARα in the myocardium. In this study, we verified the inhibitory effects of hypoxia and obesity on PPARα and examined whether WY14643 (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid), an agonist of PPARα, ameliorates myocardial mitochondrial dysfunction and protects cardiac function in obese rats under chronic persistent hypoxia.

Main Methods: Sprague-Dawley rats were randomly divided into six groups: a control group (normal chow diet, normal oxygen), a high-fat diet (HFD) group (normal oxygen), a chronic persistent hypoxia normal chow diet group, a chronic persistent hypoxia HFD group, a chronic persistent hypoxia HFD group with WY14643 treatment, and a chronic persistent hypoxia HFD group with vehicle treatment.

Key Findings: Hypoxia and obesity increased myocardial lipid accumulation, mitochondrial dysfunction, and left ventricular systolic dysfunction. Myocardial lipid metabolism-related genes, including those encoding PPARα, PPARγ coactivator 1α (PGC1α), and carnitine palmitoyl transferase 1α (CPT1α), were downregulated, while acetyl-CoA carboxylase 2 (ACC2) was upregulated under a combination of hypoxia and obesity. WY14643 upregulated PPARα, PGC1α, and CPT1α, and downregulated ACC2. WY14643 alleviated hypoxia- and obesity-induced myocardial lipid accumulation and improved mitochondrial and left ventricular systolic functions.

Significance: WY14643 improved myocardial mitochondrial and left ventricular systolic functions in obese rats under chronic persistent hypoxia. Thus, WY14643 possibly exerts its effects by regulating the PPARα pathway and shows potential as a therapeutic target for cardiovascular diseases associated with obesity and hypoxia.