ZIP12 Contributes to Hypoxic Pulmonary Hypertension by Driving Phenotypic Switching of Pulmonary Artery Smooth Muscle Cells

ZIP12, a plasmalemmal zinc transporter, reportedly promotes pulmonary vascular remodeling (PVR) by enhancing proliferation of pulmonary artery smooth muscle cells (PASMCs). However, the mechanisms of ZIP12 facilitating PASMCs proliferation remain incompletely appreciated. It has been acknowledged that proliferation-predisposing phenotypic switching of PASMCs can lead to PVR. Given that hypoxia triggers phenotypic switching of PASMCs and ZIP12 mediates PVR, this study aims to explore whether ZIP12-mediated phenotypic switching of PASMCs contributes to hypoxia-induced PVR. Rats were exposed to hypoxia (10% O2) for 3 weeks to induce PVR, and primary rat PASMCs were cultured under hypoxic condition (3% O2) for 48 hours to induce proliferation. Immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and Western blot analysis were performed to detect the expression of target mRNAs and proteins. EdU incorporation and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay were conducted to measure the proliferation of PASMCs. Hypoxia upregulated ZIP12 expression (both mRNA and protein) in pulmonary arteries and PASMCs. Knockdown of ZIP12 inhibited phenotypic switching of PASMCs induced by hypoxia. We propose that HIF-1α/ZIP12/pERK pathway could represent a novel mechanism underlying hypoxia-induced phenotypic switching of PASMCs. Therapeutic targeting of ZIP12 could be exploited to treat PVR.