Topotecan prevents hypoxia-induced pulmonary arterial hypertension and inhibits hypoxia-inducible factor-1α and TRPC channels

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.

Keywords: HIF-1α; Hypoxia; PAH; TPT; TRPC.