Yongliang Jiang1, Yumin Zhou2, Gongyong Peng2, Nian Liu1, Heshen Tian1, Dan Pan1, Lei Liu1, Xing Yang1, Chao Li1, Wen Li1, Ling Chen1, Pixin Ran3, Aiguo Dai4. 1. Respiratory Medicine, Hunan Provincial People's Hospital, Changsha, PR China. 2. State Key Lab of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China. 3. State Key Lab of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China. Electronic address: pxran@gzhmc.edu.cn. 4. Respiratory Medicine, Hunan Provincial People's Hospital, Changsha, PR China; Institute of Respiratory Medicine, Changsha Medical College, Changsha, PR China. Electronic address: daiaiguo2003@163.com.
Abstract
BACKGROUND: This study aimed to investigate the effects of topotecan (TPT) on the hypoxia-induced pulmonary arterial hypertension (PAH) in a rat model, and to explore the underlying mechanism. METHODS: The experiments were carried out in vitro using rat PASMCs and in vivo using a rat model of hypoxia-induced PAH. RESULTS: TPT significantly suppressed the hypoxia-induced upregulation of HIF-1α and TRPC1/4/6 expression both in pulmonary arterial smooth muscle cells (PASMCs) from normal rats and in pulmonary arteries from PAH model rats. Furthermore, TPT effectively inhibited intracellular Ca2+ concentration ([Ca2+]i) change (Ca2+ influx) in PASMCs from both normal rats and PAH model rats. Importantly, TPT treatment significantly inhibited the hypoxia-induced proliferation, migration and a contractile-to-synthetic phenotypic switching of normal rat PASMCs in vitro, where the effect was abrogated by overexpression of TRPC1/4/6. Furthermore, TPT administration potently attenuated the hypoxia-induced PAH-associated pulmonary arteriolar remodeling in PAH model rats, as evidenced by amelioration of elevated hemodynamic parameters, and enhanced right ventricle hypertrophy and wall thickening. CONCLUSION: TPT ameliorates the hypoxia-induced pulmonary vascular remodeling in PAH, and the mechanism is associated with TPT-mediated inhibition of hypoxia-induced upregulation of HIF-1α and TRPC1/4/6 expression, Ca2+ influx, and PASMCs proliferation.
BACKGROUND: This study aimed to investigate the effects of topotecan (TPT) on the hypoxia-induced pulmonary arterial hypertension (PAH) in a rat model, and to explore the underlying mechanism. METHODS: The experiments were carried out in vitro using ratPASMCs and in vivo using a rat model of hypoxia-induced PAH. RESULTS:TPT significantly suppressed the hypoxia-induced upregulation of HIF-1α and TRPC1/4/6 expression both in pulmonary arterial smooth muscle cells (PASMCs) from normal rats and in pulmonary arteries from PAH model rats. Furthermore, TPT effectively inhibited intracellular Ca2+ concentration ([Ca2+]i) change (Ca2+ influx) in PASMCs from both normal rats and PAH model rats. Importantly, TPT treatment significantly inhibited the hypoxia-induced proliferation, migration and a contractile-to-synthetic phenotypic switching of normal ratPASMCs in vitro, where the effect was abrogated by overexpression of TRPC1/4/6. Furthermore, TPT administration potently attenuated the hypoxia-induced PAH-associated pulmonary arteriolar remodeling in PAH model rats, as evidenced by amelioration of elevated hemodynamic parameters, and enhanced right ventricle hypertrophy and wall thickening. CONCLUSION:TPT ameliorates the hypoxia-induced pulmonary vascular remodeling in PAH, and the mechanism is associated with TPT-mediated inhibition of hypoxia-induced upregulation of HIF-1α and TRPC1/4/6 expression, Ca2+ influx, and PASMCs proliferation.
Authors: Esraa M Zeidan; Mohammad Akbar Hossain; Mahmoud El-Daly; Mohammed A S Abourehab; Mohamed M A Khalifa; Ashraf Taye Journal: J Clin Med Date: 2022-09-03 Impact factor: 4.964