RELM-β knockout inhibits the development of hypoxia-induced pulmonary hypertension through PLC-IP3R-Ca2+ signaling pathway

Abstract Purpose Pulmonary vascular remodeling (PVR) is an important pathological mechanism of hypoxia-induced pulmonary hypertension (HPH), in which the proliferation of pulmonary artery smooth muscle cells (PASMCs) plays an important role. Resistin-like molecule beta (RELM-β), a secretory protein, can promote the proliferation of PASMCs induced by hypoxia. As an important signaling molecule, Ca 2+ plays an important role in cell proliferation. RELM-β can regulate cell proliferation by changing the intracellular calcium concentration ([Ca 2+ ] i ), but the specific regulatory mechanism of RELM-β on Ca 2+ and the pathogenesis of HPH has not been fully elucidated. Methods We employed both in vivo and in vitro RELM-β knockout (RELM-β -/- ) models to examine the effects of RELM-β on pulmonary hemodynamics, PASMCs proliferation, intracellular Ca 2+ release, and associated mechanisms. Results The expression of RELM-β increased in rat HPH model and hypoxia treated PASMCs, which led to pulmonary hemodynamic changes (increased mean pulmonary artery pressure (mPAP), right ventricular hypertrophy, pulmonary artery thickening) and PASMCs proliferation. However, knockout of RELM-β had the opposite effect. RELM-β deletion decreased the expression of phospholipase C (PLC), inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R), and [Ca 2+ ] i . In addition, inhibition of PLC and IP 3 R can reduce [Ca 2+ ] i . Conclusion Our research results have confirmed the role of RELM-β as a cytokine-like growth factor in the proliferation of PASMCs and contribute to HPH. This was achieved by upregulating [Ca 2+ ] i through the PLC/IP 3 R pathway.