Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis

Francisco J. Rios; Zhi-Guo Zou; Adam P. Harvey; Katie Y. Harvey; Ryszard Nosalski; Panagiota Anyfanti; Livia L. Camargo; Silvia Lacchini; Alexey G. Ryazanov; Lillia Ryazanova; Sarah McGrath; Tomasz J. Guzik; Carl S. Goodyear; Augusto C. Montezano; Rhian M. Touyz

doi:10.1093/cvr/cvz164

Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis

Francisco J. Rios
, Zhi-Guo Zou
, Adam P. Harvey
, Katie Y. Harvey
, Ryszard Nosalski
, Panagiota Anyfanti
, Livia L. Camargo
, Silvia Lacchini
, Alexey G. Ryazanov
, Lillia Ryazanova
, Sarah McGrath
, Tomasz J. Guzik
, Carl S. Goodyear
, Augusto C. Montezano
, Rhian M. Touyz

School of Medicine, Pharmacy and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

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^+/Δkinasemice. 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 MgCl₂treatment.

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.

Original language	English
Pages (from-to)	721–735
Number of pages	15
Journal	Cardiovascular Research
Volume	116
Issue number	3
Early online date	28 Jun 2019
DOIs	https://doi.org/10.1093/cvr/cvz164
Publication status	Published - 1 Mar 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Magnesium channel
cardiac hypertrophy
vascular inflammation
cations

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10.1093/cvr/cvz164

cvz164Final published version, 1.64 MBLicence: CC BY

Cite this

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., & Touyz, R. M. (2020). Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis. Cardiovascular Research, 116(3), 721–735. https://doi.org/10.1093/cvr/cvz164

@article{dd2b845c22af49c7bbec268a7097266e,

title = "Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis",

abstract = "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.",

keywords = "Magnesium channel, cardiac hypertrophy, vascular inflammation, cations",

author = "Rios, \{Francisco J.\} and Zhi-Guo Zou and Harvey, \{Adam P.\} and Harvey, \{Katie Y.\} and Ryszard Nosalski and Panagiota Anyfanti and Camargo, \{Livia L.\} and Silvia Lacchini and Ryazanov, \{Alexey G.\} and Lillia Ryazanova and Sarah McGrath and Guzik, \{Tomasz J.\} and Goodyear, \{Carl S.\} and Montezano, \{Augusto C.\} and Touyz, \{Rhian M.\}",

year = "2020",

month = mar,

day = "1",

doi = "10.1093/cvr/cvz164",

language = "English",

volume = "116",

pages = "721–735",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "3",

}

TY - JOUR

T1 - Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis

AU - Rios, Francisco J.

AU - Zou, Zhi-Guo

AU - Harvey, Adam P.

AU - Harvey, Katie Y.

AU - Nosalski , Ryszard

AU - Anyfanti, Panagiota

AU - Camargo, Livia L.

AU - Lacchini, Silvia

AU - Ryazanov, Alexey G.

AU - Ryazanova, Lillia

AU - McGrath, Sarah

AU - Guzik, Tomasz J.

AU - Goodyear, Carl S.

AU - Montezano, Augusto C.

AU - Touyz, Rhian M.

PY - 2020/3/1

Y1 - 2020/3/1

N2 - 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.

AB - 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.

KW - Magnesium channel

KW - cardiac hypertrophy

KW - vascular inflammation

KW - cations

UR - http://europepmc.org/abstract/med/31250885

U2 - 10.1093/cvr/cvz164

DO - 10.1093/cvr/cvz164

M3 - Article

C2 - 31250885

SN - 0008-6363

VL - 116

SP - 721

EP - 735

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 3

ER -

Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis

Abstract

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Keywords

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