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Pulmonary 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 ofCnnm2 ,Hip14 ,Hip14l ,Magt1 ,Mmgt1 ,Mrs2 ,Nipa1 ,Nipa2 ,Slc41a1 ,Slc41a2 andTrpm7 ; 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 targetingSlc41a1/2, Cnnm2, and Trpm7 attenuated PASMC proliferation and migration, but promoted apoptosis; andSlc41a3 overexpression also caused similar effects. Moreover, siRNA targetingSlc41a1 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.

Magnesium Supplementation Attenuates Pulmonary Hypertension via Regulation of Magnesium Transporters