Impact of ATP synthase/coupling factor 6 in hypoxic pulmonary arterial hypertension: An experimental rat model

Authors: NANNAN LI, YUGEN SHI, JIE YIN, LI SUN, QINGSHAN ZHANg, SHUAI BAO, JUAN ZHANg, YOULEI LI, MIAOMIAO WANG, YANWEI ZHANG, MEI XUE, LEI QI, YAN LI, SUHUA YAN, XIAOLU LI

Abstract: Background/aim: Hypoxia-induced pulmonary arterial hypertension (PAH) is characterized by prostacyclin (PGI2 ) disorder, which manifests in the same manner as in monocrotaline (MCT)-induced PAH. Endogenous PGI2 inhibitor coupling factor 6 (CF6) is involved in MCT-induced PAH. This study aimed to explore the presence or absence of a correlation between hypoxia-induced PAH and CF6. Materials and methods: This study was conducted between January 2019 and June 2020. A total of 135 male Wistar rats (aged 8 weeks and weighing 200?250 g) were randomly divided into five groups: (A) control, (B) 1 week of hypoxia, (C) 2 weeks of hypoxia, (D) 3 weeks of hypoxia, and (E) 4 weeks of hypoxia. CF6 expression in both lung tissue and blood samples from the lung vasculature and tail vein was measured by western blotting, immunohistochemistry, reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay. Results: Hemodynamic and morphological changes in hypoxia-induced rats indicated PAH development. The results showed the presence of a correlation between the mRNA and protein levels of CF6 in lung tissue, activity of mitochondrial ATP synthase, and hypoxia time, and there was a significant increment in the group exposed to hypoxia for 4 weeks compared to the control group. The decrement expression of ATPase inhibitory factor 1 (IF 1) mRNA was consistent with the outcomes of ATP synthase activity in lung tissue in the 4 weeks of hypoxia group compared with the control group. However, the levels of CF6 and ATP synthase activity did not differ between blood samples from the lung vasculature and tail vein. Conclusion: In hypoxia-induced PAH, CF6 showed downregulated expression in lung tissue, but not in pulmonary vasculature and circulation. Therefore, we speculated that CF6 and ATP synthase may play important roles in hypoxia-induced PAH.

Keywords: Coupling factor 6, adenosine triphosphate synthase activity, hypoxic, pulmonary arterial hypertension

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