Resistin-like Molecule β Acts as a Mitogenic Factor in Hypoxic Pulmonary Hypertension via Ca2+ dependent PI3K/Akt/mTOR and PKC/MAPKs Signaling Pathway

BACKGROUND: Pulmonary arterial smooth muscle cells(PASMCs) proliferation plays a crucial role in Hypoxia-induced pulmonary hypertension(HPH). Previous studies have found that Resistin-like molecule β(RELM-β) up-regulated de novo in response to hypoxia in cultured primary human PASMCs(HASMCs). RELM-β has been proved to promote PASMCs proliferation and involved in pulmonary vascular remodeling of patients with PAH. However, the expression pattern, the effects, and the mechanisms of RELM-β in HPH keep unknown. METHODS: We assessed the expression pattern, mitogenetic effect, and underlying mechanism of RELM-β in the rat HPH model and HASMCs. RESULTS: Overexpression of RELM-β alone caused the hemodynamic change in the rat model of HPH, similar to that caused by chronic hypoxia, with increased mean pulmonary arterial pressure(mPAP), right ventricle hypertrophy(RVSP), and thickening of small pulmonary arterioles. Knocking down of RELM-β partially blocked the increased mPAP, RVSP, and vascular remodeling induced by hypoxia. Phosphorylated PI3K/Akt/mTOR and PKC/MAPKs proteins were significantly up- or down-regulated by RELM-β gene overexpression or silencing. Recombinant RELM-β protein increase primary cultured human PASMCs intracellular Ca 2+ concentration and promote HASMCs proliferation. The mitogenic effect of RELM-β on HASMCs and phosphorylated PI3K/Akt/mTOR and PKC/MAPKs was suppressed by Ca 2+ inhibitor. CONCLUSIONS: Our findings suggested that RELM-β acts as a cytokine-like growth factor in the development of HPH and that this process is likely mediated by the Ca 2+ dependent PI3K/Akt/mTOR and PKC/MAPKs pathway. Keywords : hypoxic pulmonary arterial hypertension; resistin-like molecule β; Ca 2+ ; pulmonary vascular remodeling; signaling pathway