Resistin-Like Molecule Beta Participates in Calcium Regulation Via Direct Interaction With CaSR and a PLC-IP3R-Dependent Mechanism in Hypoxia-Induced Pulmonary Hypertension.

The proliferation of pulmonary artery smooth muscle cells (PASMCs) is a key mechanism in hypoxic pulmonary hypertension (HPH). Resistin-like Molecule Beta (RELM-β) promotes the hypoxia-induced proliferation of PASMCs, and calcium ions (Ca²⁺) play an important role in cell proliferation. However, the mechanism by which RELM-β regulates Ca²⁺ and the pathogenesis of HPH remain unclear. We established a RELM-β-knockout (RELM-β-/-) model and assessed the mechanism by which RELM-β affects Ca2+ regulation, cell proliferation, and pulmonary haemodynamics. In the rat HPH model and hypoxia-treated PASMCs, the expression of RELM-β was increased, which led to changes in pulmonary haemodynamics (elevated right ventricular systolic pressure [RVSP], right ventricular hypertrophy, and pulmonary artery thickening) and PASMC proliferation. Conversely, after RELM-β knockout, the opposite effects were observed. RELM-β regulated the intracellular Ca²⁺ concentration ([Ca²⁺]i) through the Phospholipase C-Inositol 1,4,5-Trisphosphate Receptor (PLC-IP3R) pathway, which promoted the release of intracellular Ca²⁺ and its binding to calcium-sensing receptor (CaSR), ultimately increasing store-operated calcium entry (SOCE) and extracellular Ca²⁺ influx and promoting PASMC proliferation. RELM-β, which is a cytokine-like growth factor, plays a role in the proliferation of PASMCs and the promotion of HPH.