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Contribution of Mg2+ and Solute Carrier Family 41 to Pulmonary Hypertension in Rat Models

Pulmonary hypertension (PH) is a debilitating disease and characterized by profound vascular remodeling. Many studies indicate that it is related in part to the alterations of Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Mg2+ ion is closely related to Ca2+ ion and is the second‐most abundant divalent cation in animal cells. It is required for the regulation of diverse cellular functions, including cell growth, proliferation, and migration. The Solute Carrier 41 family (SLC41) members including A1, A2 and A3 are Mg2+ transporters, and they have been identified in lung vascular tissue. However, the changes in their expression and functions of SLC41 transporters in PH have not been examined. The present study was designed to investigate whether Mg2+ and its transporters are involved in PH development. PH rats were established by a single injection of MCT or exposed to normobaric hypoxia (CH, 10% O2) for 21 days. Another set of animals received the same treatment were fed with Mg2+ diet supplement (10 mL/kg/d) for 21 days. The expression of SLC41A1/2/3 mRNA and protein in PAs of control and PH rats with or without Mg2+ supplement were determined by Q‐PCR and Western blot. SLC41A1‐2 expressions were significantly increased in PAs of MCT or CH‐treated rats, while mRNA and protein of SLC41A3 were decreased in PH rats. Moreover, PH was attenuated and the changes in SLC41A1‐3 expression were reversed in rats treated with Mg2+ diet supplement. The roles of Mg2+ and SLC41 proteins in PASMCs proliferation and migration were further examined in PASMCs isolated from control rat. They were treated with a control sequence or a SLC41A1/2 targeting siRNA and cultured under low (0.15 mM), normal (1.2 mM) and high (4.8 mM) level of Mg2+. PASMC proliferation monitored using MTS reagent or EdU staining and, migration assessed with Transwell or wound healing assay were markedly inhibited after incubation with high Mg2+ for 48h. Furthermore, siRNA targeting SLC41A1/2 attenuated PASMC proliferation. Our results, hence, clearly show that the SLC41 transporters contribute to PH, and Mg2+ diet supplement could effectively alleviate PH; In addition, Mg2+ and SLC41A1/2 actively participate in PASMC proliferation and migration. These results provide the basis for future study on the roles of Mg2+ and its transporters in PH development.