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

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

  • Life Sci. 2021 Feb 1:266:118888. doi: 10.1016/j.lfs.2020.118888.
Jun Yan 1,  Kang Song 2,  Zhenzhong Bai 3,  Ri-Li Ge 4
Affiliations

Affiliations

  • 1 Research Center for High Altitude Medicine, Qinghai University Medical College, Xining 810001, PR China; Key Laboratory of Persistent medicine (Qinghai University), Ministry of Education, Xining 810001, PR China; Key Laboratory for Application of Persistent Medicine in Qinghai Province, Xining 810001, PR China; Cardiovascular Medicine Department, Xuzhou Medical University affiliated hospital, Xuzhou 221006, PR China.
  • 2 Endocrinology Department, Qinghai Provincial People's Hospital, Xining 810000, PR China.
  • 3 Research Center for High Altitude Medicine, Qinghai University Medical College, Xining 810001, PR China; Key Laboratory of Persistent medicine (Qinghai University), Ministry of Education, Xining 810001, PR China; Key Laboratory for Application of Persistent Medicine in Qinghai Province, Xining 810001, PR China.
  • 4 Research Center for High Altitude Medicine, Qinghai University Medical College, Xining 810001, PR China; Key Laboratory of Persistent medicine (Qinghai University), Ministry of Education, Xining 810001, PR China; Key Laboratory for Application of Persistent Medicine in Qinghai Province, Xining 810001, PR China. Electronic address: geriligao@hotmail.com.
PMID: 33310031 DOI: 10.1016/j.lfs.2020.118888
Abstract

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.

Keywords

Chronic hypoxia; Left ventricular systolic function; Mitochondria; Obesity; PPARα; WY14643.

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