Attenuating effect of magnesium on pulmonary arterial calcification in rodent models of pulmonary hypertension.

OBJECTIVE: Vascular calcification has been considered as a potential therapeutic target in pulmonary hypertension. Mg2+ has a protective role against calcification. This study aimed to investigate whether Mg2+ could alleviate pulmonary hypertension by reducing medial calcification of pulmonary arteries. METHODS: Monocrotaline (MCT)-induced and chronic hypoxia-induced pulmonary hypertension rats were given an oral administration of 10% MgSO4 (10 ml/kg per day). Additionally, we administered Mg2+ in calcified pulmonary artery smooth muscle cells (PASMCs) after incubating with ß-glycerophosphate (ß-GP, 10 mmol/l). RESULTS: In vivo, MCT-induced and chronic hypoxia-induced pulmonary hypertension indexes, including right ventricular systolic pressure, right ventricular mass index, and arterial wall thickness, as well as Alizarin Red S (ARS) staining-visualized calcium deposition, high calcium levels, and osteochondrogenic differentiation in pulmonary arteries, were mitigated by dietary Mg2+ intake. In vitro, ß-GP-induced calcium-rich deposits stained by ARS, calcium content, as well as the detrimental effects of calcification to proliferation, migration, and resistance to apoptosis of PASMCs were alleviated by high Mg2+ but exacerbated by low Mg2+. Expression levels of mRNA and protein of ß-GP-induced osteochondrogenic markers, RUNX Family Transcription Factor 2, and Msh Homeobox 2 were decreased by high Mg2+ but increased by low Mg2+; however, Mg2+ did not affect ß-GP-induced expression of SRY-Box Transcription Factor 9. Moreover, mRNA expression and protein levels of ß-GP-reduced calcification inhibitor, Matrix GLA protein was increased by high Mg2+ but decreased by low Mg2+. CONCLUSION: Mg2+ supplement is a powerful strategy to treat pulmonary hypertension by mitigating pulmonary arterial calcification as the calcification triggered physiological and pathological changes to PASMCs.

Magnesium Supplementation Attenuates Pulmonary Hypertension via Regulation of Magnesium Transporters.

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 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.