Vascular Smooth Muscle Cell Differentiation to an Osteogenic Phenotype Involves TRPM7 Modulation by Magnesium

Montezano, Augusto C; Zimmerman, Deborah; Yusuf, Hiba; Burger, Dylan; Chignalia, Andréia Z.; Wadhera, Vishal; Leeuwen, Frank N. van; Touyz, Rhian M.

doi:10.1161/hypertensionaha.110.152058

Cited by 196 publications

(173 citation statements)

References 53 publications

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“…Transient receptor potential melastatin 7 (TRPM7), a member of TRP melastatin subfamily, is a Ca 2+ -permeable nonselective cation channel [6][7][8] whose expression has been detected in VSMCs. 9,10 Through Ca 2+ signals, TRPM7 channels participate in many physiological and pathophysiological processes, including directed cell migration, 11 cell adhesion, 12 anoxic neuronal death, 13 and transdifferentiation of cardiac fibroblast. 14 Moreover, TRPM7 is essential for embryonic development, as evidenced by genetic ablation leading to embryonic lethality.…”

mentioning

confidence: 99%

Upregulation of TRPM7 Channels by Angiotensin II Triggers Phenotypic Switching of Vascular Smooth Muscle Cells of Ascending Aorta

Zhang

Wang

Fan

et al. 2012

Circulation Research

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Rationale: Angiotensin II (Ang II) has pleiotropic effects on vascular smooth muscle cells (VSMCs). It has been demonstrated to promote the proliferative phenotype of VSMCs in mouse ascending aorta, but the underlying mechanisms remain incompletely understood.Objective: The present study was designed to explore whether the Ca 2+ -permeable transient receptor potential melastatin 7 (TRPM7) channel is involved in Ang II-induced phenotype switching of ascending aortic VSMCs and to dissect the molecular mechanisms by which TRPM7 modulates VSMC phenotype. Methods and Results:As revealed by current recording, Ang II infusion increased TRPM7 whole-cell currents in ascending aortic VSMCs. The increase in TRPM7 currents was found to result from enhanced expression of TRPM7 protein rather than elevated single-channel activity (open probability and slope conductance) and/ or reduced Mg 2+-mediated channel block. Mechanistically, Ang II elevated TRPM7 expression via Ang II type 1 receptor-mediated ERK1/2 signaling. As indicated by the expression levels of VSMC differentiation marker genes, phenotypic switching of ascending aorta occurred during Ang II infusion. Meanwhile, ERK1/2-Elk-1 signaling pathway known to suppress VSMC differentiation was activated in Ang II-infused ascending aorta. Knockdown of TRPM7 with small interfering RNA established a causative role of TRPM7 in Ang II-induced phenotypic change and promotion of cell proliferation. Moreover, TRPM7 was shown to be required for Pyk2-ERK1/2-Elk-1 pathway activation by Ang II, which potentiated TRPM7 channel function and thus activated the Ca formation in the animal model of vascular injury. 5 All the evidence converges to highlight the importance of finely tuned Ca 2+ signaling in VSMC homeostasis. Transient receptor potential melastatin 7 (TRPM7), a member of TRP melastatin subfamily, is a Ca 2+ -permeable nonselective cation channel 6-8 whose expression has been detected in VSMCs. 9,10Through Ca 2+ signals, TRPM7 channels participate in many physiological and pathophysiological processes, including directed cell migration, 11 cell adhesion, 12 anoxic neuronal death, 13 and transdifferentiation of cardiac fibroblast.14 Moreover, TRPM7 is essential for embryonic development, as evidenced by genetic ablation leading to embryonic lethality. 15,16 However, the functional role of TRPM7-mediated Ca 2+ signaling in the phenotypic switching of VSMCs has not been explored.VSMCs change their phenotype in response to various environmental cues, of which angiotensin II (Ang II) has been extensively studied. Ang II exerts multiple effects on vascular smooth muscle, including contraction of arteries under normal circumstances. Nevertheless, in certain forms of hypertension, persistent elevation of Ang II level gives rise to vascular remodeling, in which growth of VSMCs plays a pivotal role. 17,18 The majority of the studies both in vitro and in vivo have demonstrated the hypertrophic effects of Ang II in rat thoracic aortic VSMCs,19,20 which are most widely used. Nonetheless, O...

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mentioning

confidence: 99%

Upregulation of TRPM7 Channels by Angiotensin II Triggers Phenotypic Switching of Vascular Smooth Muscle Cells of Ascending Aorta

Zhang

Wang

Fan

et al. 2012

Circulation Research

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“…Feeding mice with low vitamin D for 16 wk, Schmidt et al (89) observed more calcified spots in the aortic valve than those given adequate vitamin D, accompanied by higher expressions of BMP2 and Runx2. Similarly, in animal VSMCs calcification models, administration of Mg dose-dependently decreased expressions of BMP2, osteocalcin, and ALP, leading to amelioration of VSMCs calcification (44,70).…”

Section: The Possible Mechanisms For Mics-induced Ac In Ckdmentioning

confidence: 97%

MICS, an easily ignored contributor to arterial calcification in CKD patients

Zhang

Gao

Chen

et al. 2016

American Journal of Physiology-Renal Physiology

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In chronic kidney disease (CKD), simultaneous mineral and skeleton changes are prevalent, known as CKD-mineral bone disorder (CKD-MBD). Arterial calcification (AC) is a clinically important complication of CKD-MBD. It can increase arterial stiffness, which leads to severe cardiovascular events. However, current treatments have little effect on regression of AC, as its mechanisms are still unclear. There are multiple risk factors of AC, among which Malnutrition-Inflammation Complex Syndrome (MICS) is a new and crucial one. MICS, a combined syndrome of malnutrition and inflammation, generally begins at the early stage of CKD and becomes obvious in end-stage renal disease (ESRD). It was linked to reverse epidemiology and associated with increased cardiovascular mortality in ESRD patients. Recent data suggest that MICS can trigger CKD-MBD and accelerate the course of AC. In this present review, we summarize the recent understanding about the aggravating effects of MICS on AC and discuss the possible underlying mechanisms. A series of findings indicate that targeting MICS will provide a potential strategy for treating AC in CKD.

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“…Montes de Oca et al reported that Mg inhibited Wnt/β-catenin signaling pathway and reversed osteogenic transformation of VSMC [49]. Mg transport through the cell membrane mediated by transient receptor potential melastatin 7 (TRPM7) is important in VSMC calcification [49][50][51]. Previous studies have suggested that P uptake through phosphate transporter-1 (Pit-1) is also essential in calcification [52].…”

Section: Mg and Dialysis Therapymentioning

confidence: 99%

Cardiovascular disease, mortality, and magnesium in chronic kidney disease: growing interest in magnesium-related interventions

Ikee¹

2018

Ren Replace Ther

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Magnesium (Mg) is an essential element that plays pivotal roles in a number of biological processes in the human body. Hypomagnesemia is involved in the pathophysiology of hypertension, vascular calcification, and metabolic derangements including diabetes mellitus and dyslipidemia, which are all risk factors for cardiovascular disease, the leading cause of mortality and morbidity in patients with chronic kidney disease (CKD). Hypomagnesemia is also associated with the development and progression of CKD. As CKD advances, renal Mg excretion decreases and hypermagnesemia emerges in end-stage renal disease (ESRD). In addition, dialysates with high Mg concentrations, which were used in the early era of dialysis therapy, increased the risk of hypermagnesemia, and thus, the dialysate Mg composition has since been reduced. Accordingly, dialysis patients in the modern era commonly have normomagnesemia or even hypomagnesemia. The relationships between hypomagnesemia and cardiovascular disease and mortality have been increasingly reported in observational studies in CKD/ESRD. However, these relationships may be attenuated by a patient's race or region. Although dialysates with higher Mg concentrations or Mg-containing phosphate binders appear to be promising in this setting, only a few interventional studies have examined the effects of Mg supplementation on cardiovascular lesions. Furthermore, the effects of Mg supplementation on mortality have not yet been investigated as a primary end-point in randomized controlled trials. Further studies are required in order to establish the efficacy and safety of Mg in CKD patients.

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Vascular Smooth Muscle Cell Differentiation to an Osteogenic Phenotype Involves TRPM7 Modulation by Magnesium

Cited by 196 publications

References 53 publications

Upregulation of TRPM7 Channels by Angiotensin II Triggers Phenotypic Switching of Vascular Smooth Muscle Cells of Ascending Aorta

Upregulation of TRPM7 Channels by Angiotensin II Triggers Phenotypic Switching of Vascular Smooth Muscle Cells of Ascending Aorta

MICS, an easily ignored contributor to arterial calcification in CKD patients

Cardiovascular disease, mortality, and magnesium in chronic kidney disease: growing interest in magnesium-related interventions

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