Magnesium Supplementation Attenuates Pulmonary Hypertension via Regulation of Magnesium Transporters

Dan Wang, Zhuang Li Zhu, Da Cen Lin, Si Yi Zheng, Kun Han Chuang, Long Xin Gui, Ru Hui Yao, Wei Jie Zhu, James S.K. Sham, Mo Jun Lin

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)617-631
Number of pages15
JournalHypertension (Dallas, Tex. : 1979)
Volume77
Issue number2
DOIs
StatePublished - Feb 1 2021

Keywords

  • chronic hypoxia
  • hypertension, pulmonary
  • magnesium
  • monocrotaline
  • vascular remodeling

ASJC Scopus subject areas

  • Internal Medicine

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