• Dan Wang, Zhuang-Li Zhu, Da-Cen Lin, Si-Yi Zheng, Kun-Han Chuang, Long-Xin Gui, Ru-Hui Yao, Wei-Jie Zhu, ShamJames S KJSKDivision of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.S.K.S.)., and Mo-Jun Lin.
• From the Key Laboratory of Fujian Province Universities on Ion Channel and Signal Transduction in Cardiovascular Diseases, (D.W., Z.-L.Z., D.-C.L., S.-Y.Z., K.-H.C., L.-X.G., R.-H.Y., W.-J.Z., M.-J.L.), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
• Hypertension. 2021 Feb 1; 77 (2): 617-631.

AbstractPulmonary hypertension (PH) is characterized by profound vascular remodeling and altered Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Magnesium ion (Mg2+), a natural Ca2+ antagonist and a cofactor for numerous enzymes, is crucial for regulating diverse cellular functions, but its roles in PH remains unclear. Here, we examined the roles of Mg2+ and its transporters in PH development. Chronic hypoxia and monocrotaline induced significant PH in adult male rats. It was associated with a reduction of [Mg2+]i in PASMCs, a significant increase in gene expressions of Cnnm2, Hip14, Hip14l, Magt1, Mmgt1, Mrs2, Nipa1, Nipa2, Slc41a1, Slc41a2 and Trpm7; upregulation of SLC41A1, SLC41A2, CNNM2, and TRPM7 proteins; and downregulation of SLC41A3 mRNA and protein. Mg2+ supplement attenuated pulmonary arterial pressure, right heart hypertrophy, and medial wall thickening of pulmonary arteries, and reversed the changes in the expression of Mg2+ transporters. Incubation of PASMCs with a high concentration of Mg2+ markedly inhibited PASMC proliferation and migration, and increased apoptosis, whereas a low level of Mg2+ produced the opposite effects. siRNA targeting Slc41a1/2, Cnnm2, and Trpm7 attenuated PASMC proliferation and migration, but promoted apoptosis; and Slc41a3 overexpression also caused similar effects. Moreover, siRNA targeting Slc41a1 or high [Mg2+] incubation inhibited hypoxia-induced upregulation and nuclear translocation of NFATc3 in PASMCs. The results, for the first time, provide the supportive evidence that Mg2+ transporters participate in the development of PH by modulating PASMC proliferation, migration, and apoptosis; and Mg2+ supplementation attenuates PH through regulation of Mg2+ transporters involving the NFATc3 signaling pathway.

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