Magnesium Supplementation Attenuates Pulmonary Hypertension via Regulation of Magnesium Transporters

Abstract

Pulmonary hypertension (PH) is characterized by profound vascular remodeling and altered Ca 2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Magnesium ion (Mg 2+ ), a natural Ca 2+ 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 2+ 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 2+ ] 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. Mg 2+ supplement attenuated pulmonary arterial pressure, right heart hypertrophy, and medial wall thickening of pulmonary arteries, and reversed the changes in the expression of Mg 2+ transporters. Incubation of PASMCs with a high concentration of Mg 2+ markedly inhibited PASMC proliferation and migration, and increased apoptosis, whereas a low level of Mg 2+ 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 [Mg 2+ ] incubation inhibited hypoxia-induced upregulation and nuclear translocation of NFATc3 in PASMCs. The results, for the first time, provide the supportive evidence that Mg 2+ transporters participate in the development of PH by modulating PASMC proliferation, migration, and apoptosis; and Mg 2+ supplementation attenuates PH through regulation of Mg 2+ transporters involving the NFATc3 signaling pathway.

Magnesium Homeostasis in Myogenic Differentiation—A Focus on the Regulation of TRPM7, MagT1 and SLC41A1 Transporters

“…Nonetheless, the function of TRPM7 in skeletal muscle physiology and muscle cell differentiation has not been elucidated yet. SLC41A1 is expressed in smooth muscle cells and has a role in regulating their proliferation and migration [14], while presently no data are available for MagT1. As for TRPM7, it is still obscure whether SLC41A1 and MagT1 play a role in myogenic differentiation and in mature skeletal muscle.…”

High magnesium mitigates the vasoconstriction mediated by different types of calcium influx from monocrotaline‐induced pulmonary hypertensive rats

“…RVSP was more than doubled (CON: 24.76 ± 2.38 mmHg, n = 19; MCT: 58.95 ± 8.84 mmHg, n = 23, P < 0.001; Figure 1a–c) and the right heart mass ratio, RV/(LV+S), increased notably (CON: 26.82± 3.37%, n = 15; MCT: 56.25 ± 10.52%, n = 16, P < 0.001; Figure 1d). The morphometric analysis of the pulmonary artery has been detailed in previous research (Liu et al., 2012; Wang et al., 2021). All this suggests that MCT induced profound PAH.…”

“…Previous studies have documented that in the vascular rings of chronic hypoxia‐treated mice, high [Mg 2+ ] e can mitigate the endothelin‐1 (ET‐1)‐activated vasoconstriction and adjust vasorelaxation via the release of NO in the endothelial cells (Mu et al., 2018). Moreover, Mg 2+ supplementation can mitigate the progression of PAH by regulating the Mg 2+ transporters in monocrotaline (MCT)‐treated PAH rats (Wang et al., 2021), and decrease the mean pulmonary arterial pressure in experimental PAH rats (Kh et al., 2000). Besides, studies have shown that pulmonary vascular remodelling mainly occurs in the small and medium pulmonary arteries with a diameter of <500 μm and is most significant in those with a diameter of 200–300 μm (Hislop & Reid, 1978).…”

Vascular Smooth Muscle Cells Mechanosensitive Regulators and Vascular Remodeling

“…In human and Sprague-Dawley rat PASMCs with PAH, TRPM7 is downregulated, which activates the mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular-signal-regulated kinase (ERK) pathway and decreases cellular Mg 2+ levels, thus promoting SMC proliferation exacerbating PAH [59]. TRPML1 is crucial for the initiation of Ca 2+ sparks in SMCs and the regulation of vascular contractility and blood pressure, and TRPML1-knockout mice are spontaneously hypertensive [60].…”

“…In an SHR disease model, multiple isoforms of TRP channels are activated and activated TRP mediates elevated intracellular Ca 2+ and Na + [50]. In PAH, TRPM7 is downregulated to activate the MEK/ERK pathway and intracellular Mg 2+ levels are reduced [59]; in addition, mechanical stretch potentiating the Ang II type 1/EGFR/ERK-dependent signaling pathway directly regulates VSMC proliferation induced in SHR [133]. Activation of tyrosine kinase phosphorylation in SMCs in hypertension [125] and activation of the MAPK signaling pathway both promote VSMC proliferation and migration [203].…”