Magnesium Supplementation Attenuates Pulmonary Hypertension via Regulation of Magnesium Transporters.

Pulmonary hypertension (PH) is characterized by profound vascular remodeling and altered Ca homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Magnesium ion (Mg), a natural Ca 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 Mg and its transporters in PH development. Chronic hypoxia and monocrotaline induced significant PH in adult male rats. It was associated with a reduction of [Mg] in PASMCs, a significant increase in gene expressions of , , , , , , , , , and ; upregulation of SLC41A1, SLC41A2, CNNM2, and TRPM7 proteins; and downregulation of SLC41A3 mRNA and protein. Mg supplement attenuated pulmonary arterial pressure, right heart hypertrophy, and medial wall thickening of pulmonary arteries, and reversed the changes in the expression of Mg transporters. Incubation of PASMCs with a high concentration of Mg markedly inhibited PASMC proliferation and migration, and increased apoptosis, whereas a low level of Mg produced the opposite effects. siRNA targeting attenuated PASMC proliferation and migration, but promoted apoptosis; and overexpression also caused similar effects. Moreover, siRNA targeting or high [Mg] incubation inhibited hypoxia-induced upregulation and nuclear translocation of NFATc3 in PASMCs. The results, for the first time, provide the supportive evidence that Mg transporters participate in the development of PH by modulating PASMC proliferation, migration, and apoptosis; and Mg supplementation attenuates PH through regulation of Mg transporters involving the NFATc3 signaling pathway.