scholarly journals Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis

2019 ◽  
Vol 116 (3) ◽  
pp. 721-735 ◽  
Author(s):  
Francisco J Rios ◽  
Zhi-Guo Zou ◽  
Adam P Harvey ◽  
Katie Y Harvey ◽  
Ryszard Nosalski ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Cardiac Fibroblasts ◽  
Nuclear Antigen ◽  
Culture Systems ◽  
Transient Receptor Potential Melastatin ◽  
Galectin 3 ◽  
Deficient Mice

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.

Abstract 292: TRPA1 Promoting Myofibroblast Differentiation Mediate Pressure Overload-Induced Cardiac Fibrosis

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Shuang Li ◽  
Dong Han ◽  
Dachun Yang
Keyword(s):  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Gene Transfection ◽  
Pressure Overload

Background: Hypertensive ventricular remodeling is a common cause of heart failure. Activation and accumulation of cardiac fibroblasts is the key contributors to this progression. Our previous studies indicate that transient receptor potential ankyrin 1 (TRPA1), a Ca 2+ channel necessary and sufficient, play a prominent role in ventricular remodeling. However, the molecular mechanisms regulating remain poorly understood. Methods: We used TRPA1 agonists cinnamaldehyde (CA) pretreatment and TRPA1 knockout mice to understand the role of TRPA1 in ventricular remodeling of hypertensive heart. We also examine the mechanisms through gene transfection and in vitro experiments. Results: TRPA1 overexpression fully activated myofibroblast transformation, while fibroblasts lacking TRPA1 were refractory to transforming growth factor β (TGF-β) -induced transdifferentiation. TRPA1 knockout mice showed hypertensive ventricular remodeling reversal following pressure overload. We found that the TGF-β induced TRPA1 expression through calcineurin-NFAT-Dyrk1A signaling pathway via the TRPA1 promoter. Once induced, TRPA1 activates the Ca 2+ -responsive protein phosphatase calcineurin, which itself induced myofibroblast transdifferentiation. Moreover, inhibition of calcineurin prevented TRPA1-dependent transdifferentiation. Conclusion: Our study provides the first evidence that TRPA1 regulation in cardiac fibroblasts transformation in response to hypertensive stimulation. The results suggesting a comprehensive pathway for myofibroblast formation in conjunction with TGF-β, Calcineurin, NFAT and Dyrk1A. Furthermore, these data indicate that negative modulation of cardiac fibroblast TRPA1 may represent a therapeutic strategy against hypertensive cardiac remodeling.

scholarly journals Intracellular pools of DAG-activated TRPC3 channels are essential for TLR4 activation

2021 ◽  
Author(s):  
Javier Casas ◽  
Clara Meana ◽  
José Ramón López-López ◽  
Jesús Balsinde ◽  
María A. Balboa
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Receptor Potential ◽  
Central Component ◽  
Lps Challenge ◽  
Intracellular Sensing ◽  
Lipin 1 ◽  
Transient Receptor ◽  
Tlr4 Activation

ABSTRACTToll-like receptor 4, the receptor for bacterial lipopolysaccharide (LPS), drives inflammatory responses that protect against pathogens and boost the adaptive immunity. LPS responses are known to depend on calcium fluxes, but the molecular mechanisms involved are poorly understood. Here we present evidence that the transient receptor potential canonical channel 3 (TRPC3) is activated intracellularly during macrophage exposure to LPS and is essential for Ca2+ release from internal stores. In this way TRPC3 participates in cytosolic Ca2+ elevations, TLR4 endocytosis, activation of inflammatory transcription factors and cytokine upregulation. We also report that TRPC3 is activated by diacylglycerol (DAG) generated by the phosphatidic acid phosphatase lipin-1. In accord with this, lipin-1-deficient cells show reduced Ca2+ responses to LPS challenge. A cameleon indicator directed to the endoplasmic reticulum shows that this is the organelle from which TRPC3 mediates the Ca2+ release. Finally, pharmacological inhibition of TRPC3 reduces systemic inflammation induced by LPS in mice. Collectively, our study unveils a central component of LPS-triggered Ca2+ signaling that involves intracellular sensing of lipin-1-derived DAG by TRPC3.

scholarly journals Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

2016 ◽  
Vol 39 (1) ◽  
pp. 13-32 ◽  
Author(s):  
Yuanyuan Ji ◽  
Zhidong Wang ◽  
Zongfang Li ◽  
Aijun Zhang ◽  
Yaofeng Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Angiotensin Ii ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Hepatocyte Proliferation ◽  
Nuclear Antigen ◽  
Ang Ii ◽  
Hcc Cells

Background/Aims: The pathogenesis of hepatocellular carcinoma (HCC) is mainly characterized by persistent cycles of liver injury, inflammation, and compensatory hepatocyte proliferation. Angiotensin II (Ang II) behaves as an endogenous pro-inflammatory molecule playing a significant role in HCC, however, the molecular link between Ang II, proliferation and inflammation remains unclear. Methods: Human HCC cell lines (HepG-2, SMMC-7721, MHCC97-H) were incubated with Ang II at the indicated concentrations for 24, 48, 72 h. MTT, BrdU ELISA, plate colony formation assay, immunohistochemistry, ELISA, small-interfering RNA(siRNA) transfection, quantitative real-time PCR and western blot were applied to assess their functional, morphological and molecular mechanisms in HCC cell lines. Results: High expression of Ang II type 1 receptor (AT1) and low expression of AT2 in HCC cells and tissues were found. Next, Ang II could significantly enhance cell growth and proliferation. Albeit Ang II slightly increased the percentage of HCC cells in the G0/G1 phase using flow cytometry analysis, no statistically significant alterations were shown. Further studies suggested that Ang II could directly induce proliferation associated proteins C-myc and proliferating cell nuclear antigen (PCNA) expressions, and inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) productions in HCC cells. Interestingly, blocking AT1 and AT1 siRNA evidently inhibited Ang II-induced cell proliferation and inflammatory responses in HCC cells. More importantly, these effects may be mediated by AT1/PKC/NF-κB signaling pathway in HCC cell lines. Conclusions: The results propose that Ang II/AT1/PKC/NF-κB signaling pathway is necessary for proliferation and inflammation of HCC cells, which increases our understanding of the pathogenesis and provides clues for developing new strategies against Ang II-related progress of HCC.

scholarly journals Importance of the renal ion channel TRPM6 in the circadian secretion of renin to raise blood pressure

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yosuke Funato ◽  
Daisuke Yamazaki ◽  
Daisuke Okuzaki ◽  
Nobuhiko Yamamoto ◽  
Hiroaki Miki
Keyword(s):  
Blood Pressure ◽  
Transient Receptor Potential ◽  
Sympathetic Neurons ◽  
Circadian Variation ◽  
Receptor Potential ◽  
Receptor Expression ◽  
Renin Secretion ◽  
Active Period ◽  
Transient Receptor Potential Melastatin ◽  
Deficient Mice

AbstractBlood pressure has a daily pattern, with higher values in the active period. Its elevation at the onset of the active period substantially increases the risk of fatal cardiovascular events. Renin secretion stimulated by renal sympathetic neurons is considered essential to this process; however, its regulatory mechanism remains largely unknown. Here, we show the importance of transient receptor potential melastatin-related 6 (TRPM6), a Mg2+-permeable cation channel, in augmenting renin secretion in the active period. TRPM6 expression is significantly reduced in the distal convoluted tubule of hypotensive Cnnm2-deficient mice. We generate kidney-specific Trpm6-deficient mice and observe a decrease in blood pressure and a disappearance of its circadian variation. Consistently, renin secretion is not augmented in the active period. Furthermore, renin secretion after pharmacological activation of β-adrenoreceptor, the target of neuronal stimulation, is abrogated, and the receptor expression is decreased in renin-secreting cells. These results indicate crucial roles of TRPM6 in the circadian regulation of blood pressure.

scholarly journals Relationship between low magnesium status and TRPM6 expression in the kidney and large intestine

2008 ◽  
Vol 294 (6) ◽  
pp. R2001-R2007 ◽  
Author(s):  
Lusliany J. Rondón ◽  
Wouter M. Tiel Groenestege ◽  
Yves Rayssiguier ◽  
Andrzej Mazur
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
The Body ◽  
Deficient Diet ◽  
Adequate Diet ◽  
Low Magnesium ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
The Relationship

The body maintains Mg2+ homeostasis by renal and intestinal (re)absorption. However, the molecular mechanisms that mediate transepithelial Mg2+ transport are largely unknown. Transient receptor potential melastatin 6 (TRPM6) was recently identified and shown to function in active epithelial Mg2+ transport in intestine and kidney. To define the relationship between Mg2+ status and TRPM6 expression, we used two models of hypomagnesemia: 1) C57BL/6J mice fed a mildly or severely Mg2+-deficient diet, and 2) mice selected for either low (MgL) or high (MgH) erythrocyte and plasma Mg2+ status. In addition, the mice were subjected to a severely Mg2+-deficient diet. Our results show that C57BL/6J mice fed a severely Mg2+-deficient diet developed hypomagnesemia and hypomagnesuria and showed increased TRPM6 expression in kidney and intestine. When fed a Mg2+-adequate diet, MgL mice presented hypomagnesemia and hypermagnesuria, and lower kidney and intestinal TRPM6 expression, compared with MgH mice. A severely Mg2+-deficient diet led to hypomagnesemia and hypomagnesuria in both strains. Furthermore, this diet induced kidney TRPM6 expression in MgL mice, but not in MgH mice. In conclusion, as shown in C57BL/6J mice, dietary Mg2+-restriction results in increased Mg2+ (re)absorption, which is correlated with increased TRPM6 expression. In MgL and MgH mice, the inherited Mg2+ status is linked to different TRPM6 expression. The MgL and MgH mice respond differently to a low-Mg2+ diet with regard to TRPM6 expression in the kidney, consistent with genetic factors contributing to the regulation of cellular Mg2+ levels. Further studies of these mice strains could improve our understanding of the genetics of Mg2+ homeostasis.

scholarly journals TRPM4 is required for calcium oscillations downstream from the stretch-activated TRPV4 channel

2021 ◽  
Author(s):  
Oleg Yarishkin ◽  
Tam T. Phuong ◽  
Felix Vazquez-Chona ◽  
Jacques A Bertrand ◽  
Sarah Redmon ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Membrane Surface ◽  
Receptor Potential ◽  
Calcium Oscillations ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Insight Into

Transduction of mechanical information is influenced by physical, chemical and thermal cues but the molecular mechanisms through which transducer activation shapes temporal signaling remain underexplored. In the present study, electrophysiology, histochemistry and functional imaging were combined with gene silencing and heterologous expression to gain insight into calcium signaling downstream from TRPV4 (Transient Receptor Potential Vanilloid 4), a stretch-activated nonselective cation channel. We show that trabecular meshwork (TM) cells, which employ mechanotransduction to actively regulate intraocular pressure, respond to the TRPV4 agonist GSK1016790A with fluctuations in intracellular Ca2+ concentration ([Ca2+]i) and an increase in [Na+]i. [Ca2+]i oscillations coincided with a monovalent cation current that was suppressed by BAPTA, Ruthenium Red and 9-phenanthrol, an inhibitor of TRPM4 (Transient Receptor Potential Melastatin 4) channels. Accordingly, TM cells expressed TRPM4 mRNA, protein at the expected 130-150 kDa and showed punctate TRPM4 immunoreactivity at the membrane surface. Genetic silencing of TRPM4 antagonized TRPV4-evoked oscillatory signaling whereas TRPV4 and TRPM4 co-expression in HEK-293 cells reconstituted the oscillations. Membrane potential recordings indicated that TRPM4-dependent oscillations required release of Ca2+ from internal stores. 9-phenanthrol did not affect the outflow facility in mouse eyes. Collectively, our results show that TRPV4 activity initiates dynamic calcium signaling in TM cells by stimulating TRPM4 channels and intracellular Ca2+ release. These findings provide insight into the complexity of membrane-cytosolic interactions during TRPV4 signaling and may foster strategies to promote homeostatic regulation and counter pathological remodeling within the conventional outflow pathway of the mammalian eye.

Sign in / Sign up

Export Citation Format

Share Document