Abstract
AimsTransient Receptor Potential Melastatin 7 (TRPM7) cation channel is a chanzyme (channel + kinase) that influences cellular Mg2+ homeostasis and vascular signalling. However, the pathophysiological significance of TRPM7 in the cardiovascular system is unclear. The aim of this study was to investigate the role of this chanzyme in the cardiovascular system focusing on inflammation and fibrosis.Methods and resultsTRPM7-deficient mice with deletion of the kinase domain (TRPM7+/Δkinase) were studied and molecular mechanisms investigated in TRPM7+/Δkinase bone marrow-derived macrophages (BMDM) and co-culture systems with cardiac fibroblasts. TRPM7-deficient mice had significant cardiac hypertrophy, fibrosis, and inflammation. Cardiac collagen and fibronectin content, expression of pro-inflammatory mediators (SMAD3, TGFβ) and cytokines [interleukin (IL)-6, IL-10, IL-12, tumour necrosis factor-α] and phosphorylation of the pro-inflammatory signalling molecule Stat1, were increased in TRPM7+/Δkinase mice. These processes were associated with infiltration of inflammatory cells (F4/80+CD206+ cardiac macrophages) and increased galectin-3 expression. Cardiac [Mg2+]i, but not [Ca2+]i, was reduced in TRPM7+/Δkinase mice. Calpain, a downstream TRPM7 target, was upregulated (increased expression and activation) in TRPM7+/Δkinase hearts. Vascular functional and inflammatory responses, assessed in vivo by intra-vital microscopy, demonstrated impaired neutrophil rolling, increased neutrophil: endothelial attachment and transmigration of leucocytes in TRPM7+/Δkinase mice. TRPM7+/Δkinase BMDMs had increased levels of galectin-3, IL-10, and IL-6. In co-culture systems, TRPM7+/Δkinase macrophages increased expression of fibronectin, proliferating cell nuclear antigen, and TGFβ in cardiac fibroblasts from wild-type mice, effects ameliorated by MgCl2 treatment.ConclusionsWe identify a novel anti-inflammatory and anti-fibrotic role for TRPM7 and suggest that its protective effects are mediated, in part, through Mg2+-sensitive processes.
Highlights
We showed that cells deficient in the a-kinase domain of Transient Receptor Potential Melastatin 7 cation channel (TRPM7) exhibit a proinflammatory phenotype with increased expression of ICAM-1, cyclooxygenase-2 (COX-2) and plasminogen activator inhibitor-1 (PAI-1) upon aldosterone stimulation.[11]
We explored the role of macrophages in these processes and investigated putative molecular mechanisms underlying TRPM7-dependent actions using bone marrow-derived macrophages (BMDM)
Galectin (Gal)-3 is a b-galactoside-binding lectin secreted by activated macrophages and is a biomarker for both cardiac inflammation and fibrosis.[28]
Summary
Transient Receptor Potential Melastatin 7 cation channel (TRPM7) is a ubiquitously expressed channel fused to a C-terminal a-kinase domain located in intracellular vesicles and in the plasma membrane,[1,2] with important roles in vascular regulation, hypertension,[3,4] tumour progression,[5] and immune activation.[6,7] The channel is permeable primarily to Mg2þ and to Zn2þ and Ca2þ, and the a-kinase influences activity of downstream target proteins including annexin-1, calpain-II, myosin IIA, eukaryotic elongation factor 2-kinase (eEF2-k), and phospholipase Cc2 (PLCc2).[4,8] TRPM7 has autophosphorylation residues and cleavage of the a-kinase releases fragments that bind to transcription factors resulting in epigenetic modifications.[9] The essential and non-redundant function of TRPM7 in development was demonstrated in mice where TRPM7 and TRPM7 a-kinase knockout resulted in embryonic lethality.[10] We showed that cells deficient in the a-kinase domain of TRPM7 exhibit a proinflammatory phenotype with increased expression of ICAM-1, cyclooxygenase-2 (COX-2) and plasminogen activator inhibitor-1 (PAI-1) upon aldosterone stimulation.[11] TRPM7-kinase deficient heterozygous mice are viable, they develop hypomagnesaemia, vascular dysfunction and are hyper-responsive to the blood pressure-elevating effects of angiotensin II (Ang II).[3]
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