TRPM7 channel regulates ox‐LDL‐induced proliferation and migration of vascular smooth muscle cells via MEK‐ERK pathways

Abstract

Transient receptor potential melastatin 7 (TRPM7) plays a key role in the pathophysiological response of multiple cell types. However, the role of TRPM7 channels in ox-LDL-induced proliferation and migration of VSMC remains unclear. This study used the thoracic aorta VSMCs to explore the effects of ox-LDL on cell proliferation and migration and to investigate the underlying molecular mechanisms and signaling pathways. Data demonstrated that ox-LDL significantly increased TRPM7 activity, and induced VSMC proliferation and migration. VSMC proliferation and migration were inhibited by nonspecific TRPM7 blocker 2-APB or synthetic siRNA targeting TRPM7. Furthermore, the phosphorylation of ERK1/2 and MEK1/2 associated with cell proliferation and migration decreased in TRPM7-deficient VSMC. Therefore, TRPM7 may constitute a useful target for the treatment of atherosclerosis.Keywords: MEK-ERK pathways; migration; proliferation; TRPM7; VSMCs Migration and excess proliferation of vascular smooth muscle cells (VSMCs) are involved in the pathogenesis of various vascular diseases, such as atherosclerosis [1]. Oxidized low-density lipoprotein (Ox-LDL) contributes to the atherosclerotic plaque formation and progression by several mechanisms, including the induction of endothelial cell activation and dysfunction, macrophage foam cell formation, and smooth muscle cell migration and proliferation [2]. Ox-LDL significantly increases VSMC migration and proliferation through the ERK1/2 signaling pathway [3]. However, the mechanisms underlying the effect of ox-LDL on atherosclerosis are not fully understood.Ion channels participate in cell proliferation in diverse types of cells, including vascular endothelial cells [4], cancer cells [5], smooth muscle cells [6], and mesenchymal stem cells [7]. Transient receptor potential melastatin 7 (TRPM7) channel, a member of TRP channel superfamily [8], is a widely expressed nonselective divalent cation (Ca 2+ and Mg 2+ ) channel with protein serine/threonine kinase activity that regulates diverse physiological/pathological processes, such as Mg 2+ homeostasis [9,10], hypoxic neuronal injury [11], and tumor cell growth/proliferation [12]. Activating TRPM7 channels may also contribute to the physiology/pathophysiology of cardiovascular and cerebrovascular diseases, including arterial calcification [13], atrial fibrillation [14], and hypertension [6,15]. However, little is known about the role of TRPM7 channels in atherosclerosis-related vasculopathy.Studies have shown that TRPM7 channels greatly participate in growth/proliferation and nitric oxide production of vascular endothelial cells [4], angiotensin IIinduced phenotype switching, and VSMC proliferation through the ERK pathway [6]. Although the presence and potential function of TRPM7 channels have been Abbreviations 2-APB, 2-aminoethoxydiphenyl borate; ang II, angiotensin II; DMSO, dimethyl sulfoxide; MAPK, mitogen-activated protein kinase; Ox-LDL, oxidized low-density lipoprotein; PDGF, platelet-derived growth factor; PLC, phospholipase C;...

Pathological cyclic strain promotes proliferation of vascular smooth muscle cells via the ACTH/ERK/STAT3 pathway

“…ERK is an important phosphorylase kinase that can widely activate downstream molecules and is involved in the regulation of cell function. A large number of studies have shown that ERK participates in many signaling pathways regulating proliferation in VSMCs . Therefore, ERK, as a mid‐downstream signal transduction molecule, may serve as a pivotal molecule for multiple proliferation regulatory pathways.…”

Microvesicles Derived from Inflammation-Challenged Endothelial Cells Modulate Vascular Smooth Muscle Cell Functions

“…To further understand the regulatory mechanisms of EMV, we examined the Mek/Erk pathway which comprise important proteins related with the migration of VSMC (Jeong et al, 2015; Lin et al, 2016). In this study, we found that EMV increased Mek1/2 and p-Erk1/2 in HBVSMC and blockade of the Mek1/2/Erk1/2 pathway inhibited the effect of EMV on promoting migration of HBVSMC.…”

“…The results suggest that EMV promote migration of HBVSMC via activation of the Mek1/2/Erk1/2 pathway, thereby providing a probable underlying mechanism in the process of pro-atherosclerosis. The Mek-Erk pathway has been shown to be involved in VSMC proliferation and migration under an inflammatory environment (Lin et al, 2016). Nevertheless, whether it plays a role in VSMC apoptosis has not been investigated.…”

“…Additionally, the Mek-Erk pathway was reported to be involved in inflammation-induced VSMC proliferation and migration (Lin et al, 2016). Caspase-3 and Bcl-2 are important regulators involved in VSMC apoptosis (Su et al, 2015).…”

Tanshinone IIA suppresses the progression of atherosclerosis by inhibiting the apoptosis of vascular smooth muscle cells and the proliferation and migration of macrophages induced by ox-LDL

“…Some biological processes contribute to the atherosclerotic plaque formation and progression, including smooth muscle cell migration and proliferation, macrophage foam cell formation, and altered expression of cytokines and growth factors (Pirillo et al, 2013). Ox-LDL significantly promotes VSMCs migration and proliferation in intimal area through activating the ERK1/2 signaling pathway transcription factors, which is a main feature of atherosclerotic lesions (Cutini and Massheimer, 2010; Lin et al, 2016; Yang et al, 2001). In macrophages, ox-LDL is capable of targeting several scavenger receptors and induces production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, oxidative stress, and enhances chemotaxis (Sun et al, 2009).…”