Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis

Rios, F. J. et al. (2020) Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis. Cardiovascular Research, 116(3), pp. 721-735. (doi: 10.1093/cvr/cvz164) (PMID:31250885) (PMCID:PMC7252442)

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Aims: Transient 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 results: TRPM7-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. Conclusions: We 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Anyfanti, Dr Panagiota and Harvey, Dr Adam and Harvey, Dr Katie and Montezano, Dr Augusto and Zou, ZhiGuo and Lacchini, Professor Silvia and Guzik, Professor Tomasz and Nosalski, Mr Ryszard and McGrath, Sarah and Goodyear, Professor Carl and Touyz, Professor Rhian and Rios, Dr Francisco and De Lucca Camargo, Ms Livia
Authors: Rios, F. J., Zou, Z.-G., Harvey, A. P., Harvey, K. Y., Nosalski, R., Anyfanti, P., Camargo, L. L., Lacchini, S., Ryazanov, A. G., Ryazanova, L., McGrath, S., Guzik, T. J., Goodyear, C. S., Montezano, A. C., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Cardiovascular Research
Publisher:Oxford University Press
ISSN (Online):1755-3245
Published Online:28 June 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Cardiovascular Research 116:721–735
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607382Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)RG/13/7/30099RI CARDIOVASCULAR & MEDICAL SCIENCES
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES
766921P2D - Histoindex-Clinnovate Health UKRhian TouyzMedical Research Council (MRC)N/ARI CARDIOVASCULAR & MEDICAL SCIENCES
699001Glasgow Research Accelerator Collaborative Exchange (GRACE) - translating research excellence to realise solutions.Graeme MilliganMedical Research Council (MRC)MC_PC_14133RI MOLECULAR CELL & SYSTEMS BIOLOGY
607381Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762RI CARDIOVASCULAR & MEDICAL SCIENCES