Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis

Ríos, Francisco; Zou, Zhiguo; Harvey, Adam; Harvey, Katie; Nosalski, Ryszard; Anyfanti, Panagiota; Camargo, Livia L; Lacchini, Sílvia; Ryazanov, Alexey G.; Ryazanova, Lillia V.; McGrath, Sarah; Guzik, Tomasz J.; Goodyear, Carl S.; Montezano, Augusto C; Touyz, Rhian M.

doi:10.1093/cvr/cvz164

Cited by 86 publications

(107 citation statements)

References 51 publications

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“…These results indicate that TRPM7 deletion in myocytes during the developmental stage (E9.5 to E12.5) can cause impaired adult heart function, whereas deletion of TRPM7 after embryonic day 13 does not produce any effects on normal heart function [190]. Interestingly, a recent study by Rios and colleagues reported that TRPM7-deficient mice with kinase domain deletion (TRPM7 +/∆kinase ) exhibit cardiac hypertrophy, fibrosis, and inflammation [219]. It was suggested that TRPM7 plays both anti-fibrotic and anti-inflammatory roles [219].…”

Section: Trpm Channels and Cardiac Fibrosismentioning

confidence: 93%

“…Interestingly, a recent study by Rios and colleagues reported that TRPM7-deficient mice with kinase domain deletion (TRPM7 +/∆kinase ) exhibit cardiac hypertrophy, fibrosis, and inflammation [219]. It was suggested that TRPM7 plays both anti-fibrotic and anti-inflammatory roles [219]. However, since TRPM7 channel activity was impaired in the TRPM7 +/∆kinase mice [220], it is plausible that the disrupted TRPM7 channel function during the developmental stage (E9.5 to E12.5) may have contributed to the impaired heart function, resulting in the observed cardiac hypertrophy, inflammation, and fibrosis in the TRPM7 +/∆kinase mice [219].…”

Section: Trpm Channels and Cardiac Fibrosismentioning

confidence: 99%

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Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Feng

Armillei

et al. 2019

JCDD

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Cardiac fibrosis is the excessive deposition of extracellular matrix proteins by cardiac fibroblasts and myofibroblasts, and is a hallmark feature of most heart diseases, including arrhythmia, hypertrophy, and heart failure. This maladaptive process occurs in response to a variety of stimuli, including myocardial injury, inflammation, and mechanical overload. There are multiple signaling pathways and various cell types that influence the fibrogenesis cascade. Fibroblasts and myofibroblasts are central effectors. Although it is clear that Ca2+ signaling plays a vital role in this pathological process, what contributes to Ca2+ signaling in fibroblasts and myofibroblasts is still not wholly understood, chiefly because of the large and diverse number of receptors, transporters, and ion channels that influence intracellular Ca2+ signaling. Intracellular Ca2+ signals are generated by Ca2+ release from intracellular Ca2+ stores and by Ca2+ entry through a multitude of Ca2+-permeable ion channels in the plasma membrane. Over the past decade, the transient receptor potential (TRP) channels have emerged as one of the most important families of ion channels mediating Ca2+ signaling in cardiac fibroblasts. TRP channels are a superfamily of non-voltage-gated, Ca2+-permeable non-selective cation channels. Their ability to respond to various stimulating cues makes TRP channels effective sensors of the many different pathophysiological events that stimulate cardiac fibrogenesis. This review focuses on the mechanisms of Ca2+ signaling in fibroblast differentiation and fibrosis-associated heart diseases and will highlight recent advances in the understanding of the roles that TRP and other Ca2+-permeable channels play in cardiac fibrosis.

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Section: Trpm Channels and Cardiac Fibrosismentioning

confidence: 93%

Section: Trpm Channels and Cardiac Fibrosismentioning

confidence: 99%

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Feng

Armillei

et al. 2019

JCDD

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“…Importantly, treatment with anti-TGF-β antibody ameliorates progressive kidney damage via inhibition of TGF-β/Smad signaling pathway 27 . In hepatic and cardiac fibrosis, TRPM7 is upregulated by TGF-β1 stimulation and Smad2/3 phosphorylation 10,36 . In addition, a recent report showed that Smad2 is a substrate of the TRPM7 kinase 3,37 .…”

Section: Discussionmentioning

confidence: 99%

TRPM7 contributes to progressive nephropathy

Suzuki

Penner

Fleig

2020

Sci Rep

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TRPM7 belongs to the Transient Receptor Potential Melastatin family of ion channels and is a divalent cation-conducting ion channel fused with a functional kinase. TRPM7 plays a key role in a variety of diseases, including neuronal death in ischemia, cancer, cardiac atrial fibrillation, malaria invasion. TRPM7 is aberrantly over-expressed in lung, liver and heart fibrosis. It is also overexpressed after renal ischemia-reperfusion, an event that induces kidney injury and fibrosis. However, the role of TRPM7 in kidney fibrosis is unclear. Using the unilateral ureteral obstruction (UUO) mouse model, we examined whether TRPM7 contributes to progressive renal damage and fibrosis. We find that TRPM7 expression increases in UUO kidneys. Systemic application of NS8593, a known TRPM7 inhibitor, prevents kidney atrophy in UUO kidneys, retains tubular formation, and reduces TRPM7 expression to normal levels. Cell proliferation of both tubular epithelial cells and interstitial cells is reduced by NS8593 treatment in UUO kidneys, as are TGF-β1/Smad signaling events. We conclude that TRPM7 is upregulated during inflammatory renal damage and propose that pharmacological intervention targeting TRPM7 may prove protective in progressive kidney fibrosis.TRPM7 belongs to the Transient Receptor Potential (TRP) Melastatin family of ion channels, but is unique in that its ion channel domain is fused with a functional serine/threonine kinase 1 . TRPM7 was the first ion channel shown to conduct a range of divalent cations 2,3 , including physiologically essential divalent cations such as Ca 2+ , Mg 2+ , Zn 2+ , Ni 2+ , Mn 2+ , and Co 2+ . Ample evidence supports TRPM7 to be critical in regulating Mg 2+ homeostasis 1 and play a key role in a variety of diseases, including neuronal death in ischemia 4 , renal ischemia 5 , and cardiac atrial fibrillation 6 . TRPM7 is expressed ubiquitously in mammals, and is key in driving cell growth and proliferation, linking the protein to hyperproliferative diseases such cancer 1,7,8 and pulmonary, hepatic, and cardiac fibrosis 6,9-12 . Tissue fibrosis refers to a number of conditions that cause interstitial organ damage followed by inflammation and maladaptive wound healing eventually leading to fibrosis and chronic disease in the organ affected. TRPM7 overexpression leads to fibrosis through the TGF-β signaling pathway 9-11 . Recent in vitro data show that TRPM7 plays a pivotal role in progressive inflammatory and fibrotic disease by promoting excessive extracellular matrix (ECM) deposition 9 . It regulates proliferation and differentiation of fibroblasts 11 and proliferation and polarization of macrophages 13 as well as their Ca 2+ -dependent activation 14 . A recent study supports this hypothesis, as genetic suppression of TRPM7 in a kidney transplantation mouse model alleviated progressive inflammatory kidney fibrosis 15 .In the kidney, cell proliferation is a central response to injury that culminates in the development of fibrosis and renal failure. Unilateral ureteral obstruction (UUO) is a wide...

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“…Deletion of Trpm7 in mice disrupts cardiac automaticity and causes cardiac hypertrophy and fibrosis. 40,54 In ischemic cardiomyopathy, TRPM7 was significantly down regulated in the left atria and ventricle. 39 However, in non-ischemic dilated cardiomyopathy, TRPM7 was shown to be upregulated in patients with ventricular tachycardia.…”

Section: Discussionmentioning

confidence: 99%

Enhancer and promoter usage in the normal and failed human heart

Am¹,

Dellefave‐Castillo²,

Pgt³

et al. 2020

Preprint

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Word count: 5331 (excluding references and legends)Short title: Promoter and enhancer shifts in heart failure ABSTRACTThe failed heart is characterized by re-expression of a fetal gene program, which contributes to adaptation and maladaptation in heart failure. To define genomewide enhancer and promoter use in heart failure, Cap Analysis of Gene Expression (CAGE-seq) was applied to healthy and failed human left ventricles to define short RNAs associated with both promoters and enhancers. Integration of CAGE-seq data with RNA sequencing identified a combined ~17,000 promoters and ~1,500 enhancers active in healthy and failed human left ventricles. Comparing promoter usage between healthy and failed hearts highlighted promoter shifts which altered amino-terminal protein sequences. Comparing enhancer usage between healthy and failed hearts revealed a majority of differentially utilized heart failure enhancers were intronic and primarily localized within the first intron, identifying this position as a common feature associated with tissue-specific gene expression changes in the heart. This dataset defines the dynamic genomic regulatory landscape underlying heart failure and serves as an important resource for understanding genetic contributions to cardiac dysfunction. Wang from the Northwestern University sequencing core and Yujiro Takegami from DNAFORM for their excellent technical support. AG conducted the analysis and drafted the mansuscript. LDC secured patient consent and genotype information. PP assisted with genotyping. JAW provided access to control samples. DYB and MJP provided helpful advice and commentary and assisted with interpretation. MAN and EMM assisted with analysis, writing and editing the manuscript.

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Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis

Cited by 86 publications

References 51 publications

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

TRPM7 contributes to progressive nephropathy

Enhancer and promoter usage in the normal and failed human heart

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