Hypoxia-induced autophagy activation through NF-κB pathway regulates cell proliferation and migration to induce pulmonary vascular remodeling.

Objectives: This study aimed to investigate whether autophagy mediated cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia and to validate the underlying mechanism.

Methods: The rat model of chronic hypoxia-induced pulmonary vascular remodeling was established. Rat primary PASMCs were isolated and cultured in vitro in hypoxia or normoxia to explore the underlying mechanism.

Results: Hypoxia exposure for 21 days induced pulmonary vascular remodeling in rats, accompanied by enhanced proliferation and decreased apoptosis, as well as induced expression of autophagic marker LC3II in their lungs. Furthermore, in vitro assays revealed that hypoxia exposure significantly promoted cell proliferation and migration, but inhibited apoptosis of PASMCs compared with normoxia treatment. Besides, hypoxia exposure led to an increase of cell fractions in S phase and a decrease in G0/G1 of PASMCs, whereas had no significant effect on cell population in G2/M phase. Moreover, the autophagy inhibitor 3-MA significantly decreased the hypoxia-induced upregulated expression of LC3II in PASMCs and abrogated the effect of hypoxia on cell proliferation, cell apoptosis, cell cycle, and cell migration of PASMCs. Additionally, inhibition of NF-κB pathway by PDTC suppressed the hypoxia-induced upregulation of NF-κB activity, LC3II, and cell cycle regulators (cyclin D1, CDK4, and CDK6) in PASMCs, and abolished the hypoxia-mediated regulation of cell proliferation, apoptosis, cycle, and migration of PASMCs.

Conclusion: In summary, hypoxia could induce autophagy activation through NF-κB pathway, and thereby regulate cell proliferation and migration to induce pulmonary vascular remodeling.