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Knockdown of transient receptor potential melastatin 7 (TRPM7) inhibits the proliferation induced by angiotensin II (Ang II) in cardiac fi bro4. Knockdown of transient receptor potential melastatin 7 (TRPM7) inhibits the proliferation induced by angiotensin II (Ang II) in cardiac fi brotransient receptor potential melastatin 7 (TRPM7) inhibits the proliferation induced by angiotensin II (Ang II) in cardiac fi broinhibits the proliferation induced by angiotensin II (Ang II) in cardiac fi broangiotensin II (Ang II) in cardiac fi broin cardiac fi brocardiac fibroblasts (CFs). (A and B) Western blotting showed that Ang II markedly increased Ki-67 and PCNA protein expression levels which represent cell proliferation ability ( * p<0.05 vs. NC), while TRPM7-siRNA abrogated the Ang II effect ( # p<0.05 vs. Ang II). (C) CCK-8 assay showed the same trends ( * p<0.05 vs. NC; # p<0.05 vs. Ang II). TRPM7-siRNA inhibited Ang II-elicited CF proliferation ( # p<0.01 vs. Ang II), as well as the proliferation of CFs in basal condition ( & p<0.05 vs. NC).
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Transient receptor potential melastatin 7 (TRPM7), a bifunctional channel protein owning both cation permeability and kinase activity, plays an important role in the pathophysiological process of many cell types, such as vascular smooth muscle cells, human glioma cells and mouse cortical astrocytes. However, whether TRPM7 channels play a key role i...
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... we aimed to ascertain for the first time whether TRPM7 channels play a critical role in the proliferation of CFs. Firstly, we used CCK-8 assay to detect the proliferation abilities of CFs under various conditions. We found that pretreatment of CFs with 1 µM/l Ang II for 24 h significantly increased the proliferative ability of CFs (p<0.05 vs. NC) (Fig. 4C). Downregulation of TRPM7 in CFs with Ad-TRPM7-siRNA markedly reduced Ang II-induced CF proliferation (p<0.05 vs. Ang II) (Fig. 4C). To further confirm the role of TRPM7 channels in CF proliferation, cell cycle- related regulatory protein Ki-67 and proliferating cell nuclear antigen (PCNA) were employed to assess the CF proliferative ...
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... CCK-8 assay to detect the proliferation abilities of CFs under various conditions. We found that pretreatment of CFs with 1 µM/l Ang II for 24 h significantly increased the proliferative ability of CFs (p<0.05 vs. NC) (Fig. 4C). Downregulation of TRPM7 in CFs with Ad-TRPM7-siRNA markedly reduced Ang II-induced CF proliferation (p<0.05 vs. Ang II) (Fig. 4C). To further confirm the role of TRPM7 channels in CF proliferation, cell cycle- related regulatory protein Ki-67 and proliferating cell nuclear antigen (PCNA) were employed to assess the CF proliferative rate. Fig. 4A and B shows that Ang II intervention prominently promoted Ki-67 and PCNA protein expression and treatment with ...
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... 4C). Downregulation of TRPM7 in CFs with Ad-TRPM7-siRNA markedly reduced Ang II-induced CF proliferation (p<0.05 vs. Ang II) (Fig. 4C). To further confirm the role of TRPM7 channels in CF proliferation, cell cycle- related regulatory protein Ki-67 and proliferating cell nuclear antigen (PCNA) were employed to assess the CF proliferative rate. Fig. 4A and B shows that Ang II intervention prominently promoted Ki-67 and PCNA protein expression and treatment with Ad-TRPM7-siRNA notably inhibited Ang II-elicited protein expression in the CFs (p<0.01 vs. NC; p<0.01 vs. Ang II) (Fig. 4B). In addition, we found that TRPM7-siRNA not only inhibited Ang II-elicited CF proliferation (p<0.01 ...
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... protein Ki-67 and proliferating cell nuclear antigen (PCNA) were employed to assess the CF proliferative rate. Fig. 4A and B shows that Ang II intervention prominently promoted Ki-67 and PCNA protein expression and treatment with Ad-TRPM7-siRNA notably inhibited Ang II-elicited protein expression in the CFs (p<0.01 vs. NC; p<0.01 vs. Ang II) (Fig. 4B). In addition, we found that TRPM7-siRNA not only inhibited Ang II-elicited CF proliferation (p<0.01 vs. Ang II) ( Fig. 4B and C) but also suppressed the proliferation of CFs in basal condition (p<0.05 vs. NC) ( Fig. 4B and C). Together, these results indicated that TRPM7 channels are involved in the proliferation of CFs, whereas ...
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... and B shows that Ang II intervention prominently promoted Ki-67 and PCNA protein expression and treatment with Ad-TRPM7-siRNA notably inhibited Ang II-elicited protein expression in the CFs (p<0.01 vs. NC; p<0.01 vs. Ang II) (Fig. 4B). In addition, we found that TRPM7-siRNA not only inhibited Ang II-elicited CF proliferation (p<0.01 vs. Ang II) ( Fig. 4B and C) but also suppressed the proliferation of CFs in basal condition (p<0.05 vs. NC) ( Fig. 4B and C). Together, these results indicated that TRPM7 channels are involved in the proliferation of CFs, whereas knockdown of TRPM7 by siRNA inhibited the proliferation induced by Ang ...
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... with Ad-TRPM7-siRNA notably inhibited Ang II-elicited protein expression in the CFs (p<0.01 vs. NC; p<0.01 vs. Ang II) (Fig. 4B). In addition, we found that TRPM7-siRNA not only inhibited Ang II-elicited CF proliferation (p<0.01 vs. Ang II) ( Fig. 4B and C) but also suppressed the proliferation of CFs in basal condition (p<0.05 vs. NC) ( Fig. 4B and C). Together, these results indicated that TRPM7 channels are involved in the proliferation of CFs, whereas knockdown of TRPM7 by siRNA inhibited the proliferation induced by Ang ...
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... there appears to be no investigation concentrated on the role of TRPM7 channels in CF proliferation and differentiation. In our in vitro study, we observed that CFs passaged to 3-5 gener- ations exhibited a certain capacity for proliferation (assessed by monitoring CCK-8 and the expression level of Ki-67 and PCNA) and differentiation (assessed by monitoring the expres- sion level of α-SMA using immunofluorescence assay and western blot technique) which was markedly increased after Ang II stimulation along with an increase in TRPM7 channel mRNA and protein expression (Figs. 4 and 5). After interven- tion with Ad-TRPM7-siRNA, the increase in Ang II-elicited proliferation and differentiation in CFs was evidently dimin- ished (Figs. 4 and 5). ...
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... of α-SMA using immunofluorescence assay and western blot technique) which was markedly increased after Ang II stimulation along with an increase in TRPM7 channel mRNA and protein expression (Figs. 4 and 5). After interven- tion with Ad-TRPM7-siRNA, the increase in Ang II-elicited proliferation and differentiation in CFs was evidently dimin- ished (Figs. 4 and 5). In addition, using electrophysiological approaches, we found that the TRPM7 currents recorded in the CF cell membrane also manifested a similar trend of change (Fig. 3). These results provided a direct relation between Ang II-induced CF proliferation, differentiation and TRPM7 currents and TRPM7 channels and therefore demonstrated ...
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... we aimed to ascertain for the first time whether TRPM7 channels play a critical role in the proliferation of CFs. Firstly, we used CCK-8 assay to detect the proliferation abilities of CFs under various conditions. We found that pretreatment of CFs with 1 µM/l Ang II for 24 h significantly increased the proliferative ability of CFs (p<0.05 vs. NC) (Fig. 4C). Downregulation of TRPM7 in CFs with Ad-TRPM7-siRNA markedly reduced Ang II-induced CF proliferation (p<0.05 vs. Ang II) (Fig. 4C). To further confirm the role of TRPM7 channels in CF proliferation, cell cyclerelated regulatory protein Ki-67 and proliferating cell nuclear antigen (PCNA) were employed to assess the CF proliferative ...
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... CCK-8 assay to detect the proliferation abilities of CFs under various conditions. We found that pretreatment of CFs with 1 µM/l Ang II for 24 h significantly increased the proliferative ability of CFs (p<0.05 vs. NC) (Fig. 4C). Downregulation of TRPM7 in CFs with Ad-TRPM7-siRNA markedly reduced Ang II-induced CF proliferation (p<0.05 vs. Ang II) (Fig. 4C). To further confirm the role of TRPM7 channels in CF proliferation, cell cyclerelated regulatory protein Ki-67 and proliferating cell nuclear antigen (PCNA) were employed to assess the CF proliferative rate. Fig. 4A and B shows that Ang II intervention prominently promoted Ki-67 and PCNA protein expression and treatment with ...
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... (Fig. 4C). Downregulation of TRPM7 in CFs with Ad-TRPM7-siRNA markedly reduced Ang II-induced CF proliferation (p<0.05 vs. Ang II) (Fig. 4C). To further confirm the role of TRPM7 channels in CF proliferation, cell cyclerelated regulatory protein Ki-67 and proliferating cell nuclear antigen (PCNA) were employed to assess the CF proliferative rate. Fig. 4A and B shows that Ang II intervention prominently promoted Ki-67 and PCNA protein expression and treatment with Ad-TRPM7-siRNA notably inhibited Ang II-elicited protein expression in the CFs (p<0.01 vs. NC; p<0.01 vs. Ang II) (Fig. 4B). In addition, we found that TRPM7-siRNA not only inhibited Ang II-elicited CF proliferation (p<0.01 ...
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... protein Ki-67 and proliferating cell nuclear antigen (PCNA) were employed to assess the CF proliferative rate. Fig. 4A and B shows that Ang II intervention prominently promoted Ki-67 and PCNA protein expression and treatment with Ad-TRPM7-siRNA notably inhibited Ang II-elicited protein expression in the CFs (p<0.01 vs. NC; p<0.01 vs. Ang II) (Fig. 4B). In addition, we found that TRPM7-siRNA not only inhibited Ang II-elicited CF proliferation (p<0.01 vs. Ang II) ( Fig. 4B and C) but also suppressed the proliferation of CFs in basal condition (p<0.05 vs. NC) ( Fig. 4B and C). Together, these results indicated that TRPM7 channels are involved in the proliferation of CFs, whereas ...
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... and B shows that Ang II intervention prominently promoted Ki-67 and PCNA protein expression and treatment with Ad-TRPM7-siRNA notably inhibited Ang II-elicited protein expression in the CFs (p<0.01 vs. NC; p<0.01 vs. Ang II) (Fig. 4B). In addition, we found that TRPM7-siRNA not only inhibited Ang II-elicited CF proliferation (p<0.01 vs. Ang II) ( Fig. 4B and C) but also suppressed the proliferation of CFs in basal condition (p<0.05 vs. NC) ( Fig. 4B and C). Together, these results indicated that TRPM7 channels are involved in the proliferation of CFs, whereas knockdown of TRPM7 by siRNA inhibited the proliferation induced by Ang ...
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... with Ad-TRPM7-siRNA notably inhibited Ang II-elicited protein expression in the CFs (p<0.01 vs. NC; p<0.01 vs. Ang II) (Fig. 4B). In addition, we found that TRPM7-siRNA not only inhibited Ang II-elicited CF proliferation (p<0.01 vs. Ang II) ( Fig. 4B and C) but also suppressed the proliferation of CFs in basal condition (p<0.05 vs. NC) ( Fig. 4B and C). Together, these results indicated that TRPM7 channels are involved in the proliferation of CFs, whereas knockdown of TRPM7 by siRNA inhibited the proliferation induced by Ang ...
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... there appears to be no investigation concentrated on the role of TRPM7 channels in CF proliferation and differentiation. In our in vitro study, we observed that CFs passaged to 3-5 generations exhibited a certain capacity for proliferation (assessed by monitoring CCK-8 and the expression level of Ki-67 and PCNA) and differentiation (assessed by monitoring the expression level of α-SMA using immunofluorescence assay and western blot technique) which was markedly increased after Ang II stimulation along with an increase in TRPM7 channel mRNA and protein expression (Figs. 4 and 5). After intervention with Ad-TRPM7-siRNA, the increase in Ang II-elicited proliferation and differentiation in CFs was evidently diminished (Figs. 4 and 5). ...
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... of α-SMA using immunofluorescence assay and western blot technique) which was markedly increased after Ang II stimulation along with an increase in TRPM7 channel mRNA and protein expression (Figs. 4 and 5). After intervention with Ad-TRPM7-siRNA, the increase in Ang II-elicited proliferation and differentiation in CFs was evidently diminished (Figs. 4 and 5). In addition, using electrophysiological approaches, we found that the TRPM7 currents recorded in the CF cell membrane also manifested a similar trend of change (Fig. 3). These results provided a direct relation between Ang II-induced CF proliferation, differentiation and TRPM7 currents and TRPM7 channels and therefore demonstrated ...
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... 11 One of the first attempts to estimate the main currents and their underlying channels in CFs was made by Li et al. 12 They reported that human ventricular fibroblasts contain the following currents: a large conductance Ca 2+ -activated K + current (BK Ca ) 13 expressed in 88% of fibroblasts and represented by K Ca .1.1 channel; two types of voltage-gated Na + currents (I Na ) with different characteristics, represented by Na V 1.2, Na V 1.3, Na V 1.6, and Na V 1.7 channels for I Na.TTX and Na V 1.5 channels for I Na.TTXR expressed in 61% of CFs; a delayed rectifier K + current (I KDR ), represented by Kv1.5, and Kv1.6 channels registered in 15% of CFs; a transient outward K + current (I to ) represented by Kv4.2, and Kv4.3 channels registered in 14% of CFs, an inward rectifier K + current (IK ir ) represented by K ir 2.1 and K ir 2.3 channels registered in 24% of CFs, and chloride current (I Cl ) represented by Cl nc 3 channels registered in 7% of CFs. 12 Another kind of channel identified in CFs is transient receptor potential (TRP) channels. [14][15][16][17][18][19][20][21][22][23][24] These channels respond weekly to changes in voltage and can usually be turned on by different ligands, the accumulation of metabolites inside the cell, oxidative stress, thermal stimuli, or mechanical stimulation. 14 The presence of TRPC2, TRPC3, and TRPC5 (canonical subtype) channel transcripts was shown in rat ventricle fibroblasts. ...
... 17 TRPC7 channels probably participate in many cell metabolic processes and can be inactivated by phospholipase C. 16 Three isoforms of TRPM channels (melastatin subtype) were found in CFs: TRPM2, TRPM4, and TRPM7. [20][21][22] Simard et al. found that Ca 2+ -activated TRPM4 channels are very important for the growth of atrial fibroblasts in humans. 21 Overexpression of TRPM4 in human ventricle fibroblasts is probably one of the reasons for cardiac fibrogenesis in some diseases. ...
... 21 The presence of TRPM7 in CFs has been shown to have a key role in the response to angiotensin II. 22 In addition, during atrial fibrillation, these channels contribute to transforming growth factor β1 (TGF-β1)-induced fibrogenesis since they are the major Ca 2+ -permeable channel in human atrial fibroblasts. 22 TRPV2, TRPV3, and TRPV4 channels (vanilloid subtypes) are expressed in CFs. ...
Human cardiac fibroblasts (HCFs) have mRNA transcripts that encode different mechanosensitive ion channels and channel regulatory proteins whose functions are not known yet. The primary goal of this work was to define the mechanosensitive ion channelome of HCFs. The most common type of cationic channel is the transient receptor potential (TRP) family, which is followed by the TWIK-related K ⁺ channel (TREK), transmembrane protein 63 (TMEM63), and PIEZO channel (PIEZO) families. In the sodium-dependent NON-voltage-gated channel (SCNN) subfamily, only SCNN1D was shown to be highly expressed. Particular members of the acid-sensing ion channel (ASIC) (ASIC1 and ASIC3) subfamilies were also significantly expressed. The transcripts per kilobase million (TPMs) for Piezo 2 were almost 100 times less abundant than those for Piezo 1. The tandem of P domains in a weak inward rectifying K ⁺ channel (TWIK)-2 channel, TWIK-related acid-sensitive K ⁺ channel (TASK)-5, TASK-1, and the TWIK-related K1 (TREK-1) channel were the four most prevalent types in the K2P subfamily. The highest expression in the TRPP subfamily was found for PKD2 and PKD1, while in the TRPM subfamily, it was found for TRPM4, TRPM7, and TRPM3. TRPV2, TRPV4, TRPV3, and TRPV6 (all members of the TRPV subfamily) were also substantially expressed. A strong expression of the TRPC1, TRPC4, TRPC6, and TRPC2 channels and all members of the TRPML subfamily (MCOLN1, MCOLN2, and MCOLN3) was also shown. In terms of the transmembrane protein 16 (TMEM16) family, the HCFs demonstrated significant expression of the TMEM16H, TMEM16F, TMEM16J, TMEM16A, and TMEM16G channels. TMC3 is the most expressed channel in HCFs of all known members of the transmembrane channel-like protein (TMC) family. This analysis of the mechanosensitive ionic channel transcriptome in HCFs: (1) agrees with previously documented findings that all currently identified mechanosensitive channels play a significant and well recognized physiological function in elucidating the mechanosensitive characteristics of HCFs; (2) supports earlier preliminary reports that point to the most common expression of the TRP mechanosensitive family in HCFs; and (3) points to other new mechanosensitive channels (TRPC1, TRPC2, TWIK-2, TMEM16A, ASIC1, and ASIC3).
... In primary cultured fibroblasts, oxidative stress induces the increase of fibrotic α-SMA and type I collagen by extracellular Ca 2+ and TRPM7-mediated Ca 2+ influx, which is accompanied by increased phosphorylation of ERK1/2 (Ahn et al., 2020). Besides, after incubating rat cardiac fibroblasts with angiotensin II, the expression level of TRPM7 protein, collagen I and III increase, promoting the occurrence of fibrosis, while the knockdown of TRPM7 protein can inhibit the differentiation of fibroblasts and the occurrence of fibrosis Li et al., 2017). TRPA1 is expressed in CFs (Li et al., 2019). ...
Cardiac fibrosis is defined as excessive deposition of extracellular matrix (ECM) in pathological conditions. Cardiac fibroblasts (CFs) activated by injury or inflammation differentiate into myofibroblasts (MFs) with secretory and contractile functions. In the fibrotic heart, MFs produce ECM which is composed mainly of collagen and is initially involved in maintaining tissue integrity. However, persistent fibrosis disrupts the coordination of excitatory contractile coupling, leading to systolic and diastolic dysfunction, and ultimately heart failure. Numerous studies have demonstrated that both voltage- and non-voltage-gated ion channels alter intracellular ion levels and cellular activity, contributing to myofibroblast proliferation, contraction, and secretory function. However, an effective treatment strategy for myocardial fibrosis has not been established. Therefore, this review describes the progress made in research related to transient receptor potential (TRP) channels, Piezo1, Ca2+ release-activated Ca2+ (CRAC) channels, voltage-gated Ca2+ channels (VGCCs), sodium channels, and potassium channels in myocardial fibroblasts with the aim of providing new ideas for treating myocardial fibrosis.
... The channel has been studied in freshly isolated and cultured human atrial fibroblasts (Du et al., 2010), mouse cultured fibroblasts (Li et al., 2008;, and rat isolated and cultured fibroblasts (Yu N. et al., 2014;Guo et al., 2014; Frontiers in Physiology frontiersin.org et al., Li et al., 2017;Lu et al., 2017;Wu et al., 2018;. The evidence from changes in TRPM7 channel activity and the expression of protein or mRNA in cardiac fibroblasts indicate that, in general, the channel promotes fibroblast proliferation and fibroblast-myofibroblast trans-differentiation (Du et al., 2010;Guo et al., 2014;Li et al., 2017;Lu et al., 2017;Wu et al., 2018) as well as fibrinogenesis (Du et al., 2010;Guo et al., 2014;Zhou et al., 2015;Li et al., 2017;Lu et al., 2017;Wu et al., 2018). ...
... et al., Li et al., 2017;Lu et al., 2017;Wu et al., 2018;. The evidence from changes in TRPM7 channel activity and the expression of protein or mRNA in cardiac fibroblasts indicate that, in general, the channel promotes fibroblast proliferation and fibroblast-myofibroblast trans-differentiation (Du et al., 2010;Guo et al., 2014;Li et al., 2017;Lu et al., 2017;Wu et al., 2018) as well as fibrinogenesis (Du et al., 2010;Guo et al., 2014;Zhou et al., 2015;Li et al., 2017;Lu et al., 2017;Wu et al., 2018). Such TRPM7-mediated profibrotic effects occur in cardiac disease conditions such as myocardial infarction (Li et al., 2008), atrial fibrillation (Du et al., 2010), and sick sinus syndrome as well as following receptor-mediated cardiac stimulation with agonists like angiotensin II Zhou et al., 2015;Li et al., 2017; and isoprenaline (Li et al., 2017;Wu et al., 2018). ...
... et al., Li et al., 2017;Lu et al., 2017;Wu et al., 2018;. The evidence from changes in TRPM7 channel activity and the expression of protein or mRNA in cardiac fibroblasts indicate that, in general, the channel promotes fibroblast proliferation and fibroblast-myofibroblast trans-differentiation (Du et al., 2010;Guo et al., 2014;Li et al., 2017;Lu et al., 2017;Wu et al., 2018) as well as fibrinogenesis (Du et al., 2010;Guo et al., 2014;Zhou et al., 2015;Li et al., 2017;Lu et al., 2017;Wu et al., 2018). Such TRPM7-mediated profibrotic effects occur in cardiac disease conditions such as myocardial infarction (Li et al., 2008), atrial fibrillation (Du et al., 2010), and sick sinus syndrome as well as following receptor-mediated cardiac stimulation with agonists like angiotensin II Zhou et al., 2015;Li et al., 2017; and isoprenaline (Li et al., 2017;Wu et al., 2018). ...
Cardiac fibroblasts make up a major proportion of non-excitable cells in the heart and contribute to the cardiac structural integrity and maintenance of the extracellular matrix. During myocardial injury, fibroblasts can be activated to trans-differentiate into myofibroblasts, which secrete extracellular matrix components as part of healing, but may also induce cardiac fibrosis and pathological cardiac structural and electrical remodeling. The mechanisms regulating such cellular processes still require clarification, but the identification of transient receptor potential (TRP) channels in cardiac fibroblasts could provide further insights into the fibroblast-related pathophysiology. TRP proteins belong to a diverse superfamily, with subgroups such as the canonical (TRPC), vanilloid (TRPV), melastatin (TRPM), ankyrin (TRPA), polycystin (TRPP), and mucolipin (TRPML). Several TRP proteins form non-selective channels that are permeable to cations like Na ⁺ and Ca ²⁺ and are activated by various chemical and physical stimuli. This review highlights the role of TRP channels in cardiac fibroblasts and the possible underlying signaling mechanisms. Changes in the expression or activity of TRPs such as TRPCs, TRPVs, TRPMs, and TRPA channels modulate cardiac fibroblasts and myofibroblasts, especially under pathological conditions. Such TRPs contribute to cardiac fibroblast proliferation and differentiation as well as to disease conditions such as cardiac fibrosis, atrial fibrillation, and fibroblast metal toxicity. Thus, TRP channels in fibroblasts represent potential drug targets in cardiac disease.
... In fact, it was observed to be required for TGF-β induced differentiation of cardiac fibroblasts into myofibroblasts, also confirmed in the context of pulmonary fibrosis. However, also TRPC6 and TRPM7 were addressed to cardiac fibroblasts activation [87,88]. In addition, even cardiomyocytes expressing TRPM4 were found able to contribute in cardiac fibrosis [89]. ...
Fibrotic tissues share many common features with neoplasms where there is an increased stiffness of the extracellular matrix (ECM). In this review, we present recent discoveries related to the role of the mechanosensitive ion channel Piezo1 in several diseases, especially in regulating tumor progression, and how this can be compared with cardiac mechanobiology. Based on recent findings, Piezo1 could be upregulated in cardiac fibroblasts as a consequence of the mechanical stress and pro-inflammatory stimuli that occurs after myocardial injury, and its increased activity could be responsible for a positive feedback loop that leads to fibrosis progression. The increased Piezo1-mediated calcium flow may play an important role in cytoskeleton reorganization since it induces actin stress fibers formation, a well-known characteristic of fibroblast transdifferentiation into the activated myofibroblast. Moreover, Piezo1 activity stimulates ECM and cytokines production, which in turn promotes the phenoconversion of adjacent fibroblasts into new myofibroblasts, enhancing the invasive character. Thus, by assuming the Piezo1 involvement in the activation of intrinsic fibroblasts, recruitment of new myofibroblasts, and uncontrolled excessive ECM production, a new approach to blocking the fibrotic progression can be predicted. Therefore, targeted therapies against Piezo1 could also be beneficial for cardiac fibrosis.
... These channels differ in tissue distribution, cation selectivity, and activating mechanisms, and have been implicated in a diverse array of cellular functions, including cell proliferation, cell invasion, temperature sensing, magnesium homeostasis and taste [86,108]. Dysregulation of some TRPM channels contributes to cancer promotion, cerebral ischemiareperfusion injury and cardiac fibrosis [108][109][110][111][112][113]. Within the heart, transcriptomic analysis of mouse cardiac tissue has identified only TRPM4 and TRPM7 as being expressed within the atrial myocardium, while TRPM1, 3, 4, 6 and 7 are expressed within the ventricular myocardium [114]. ...
... In relation to the heart, TRPM7 expression in humans, rodents, and zebra fish has been detected in myocytes, the sinus node, and both atrial and ventricular fibroblasts [109,121,131,132], as well as infiltrating immune cells in mice [129]. TRPM7's cardioprotective function may principally be due to homeostatic regulation of cellular Mg 2+ rather than Ca 2+ levels [130]; while TRPM7 regulation of Ca 2+ levels have been implicated in cardiac fibrosis [109][110][111]133]. ...
... Current research indicates that TRPM7 expression promotes CF proliferation and differentiation. TGF-β1 in human CF, [109] and Ang II, hydrogen peroxide, hypoxia, and isoproterenol treatment in rat hearts [110][111][112][113] all promote TRPM7 activation and subsequent increases in α-SMA and collagen synthesis in CF. However, TRPM7 has yet to be demonstrated to respond to mechanical stimuli in driving the MF phenotype. ...
Cardiac fibroblasts (CF) play a pivotal role in preserving myocardial function and integrity of the heart tissue after injury, but also contribute to future susceptibility to heart failure. CF sense changes to the cardiac environment through chemical and mechanical cues that trigger changes in cellular function. In recent years, mechanosensitive ion channels have been implicated as key modulators of a range of CF functions that are important to fibrotic cardiac remodelling, including cell proliferation, myofibroblast differentiation, extracellular matrix turnover and paracrine signalling. To date, seven mechanosensitive ion channels are known to be functional in CF: the cation non-selective channels TRPC6, TRPM7, TRPV1, TRPV4 and Piezo1, and the potassium-selective channels TREK-1 and KATP. This review will outline current knowledge of these mechanosensitive ion channels in CF, discuss evidence of the mechanosensitivity of each channel, and detail the role that each channel plays in cardiac remodelling. By better understanding the role of mechanosensitive ion channels in CF, it is hoped that therapies may be developed for reducing pathological cardiac remodelling.
... In TRPM7 kinase-deficient mice, Ang II-induced cardiac hypertrophy, interstitial fibrosis and left ventricular dysfunction are amplified (23). However, downregulation of TRPM7 attenuated Ang II-induced CF proliferation, differentiation, ECM production and accumulation (53,87). The TRPM7 Ca 2+ current, as well as the protein expression levels of TRPM7 and collagen III, initially increases and then later decreases under optimal Ang II concentrations for inducing cardiac fibrosis (88). ...
Cardiac fibrosis is a hallmark of cardiac remodeling associated with nearly all forms of heart disease. Clinically, no effective therapeutic drugs aim to inhibit cardiac fibrosis, owing to the complex etiological heterogeneity and pathogenesis of this disease. A two-in-one protein structure, a ubiquitous expression profile and unique biophysical characteristics enable the involvement of transient receptor potential melastatin-subfamily member 7 (TRPM7) in the pathogenesis and development of fibrosis-related cardiac diseases, such as heart failure (HF), cardiomyopathies, arrhythmia and hyperaldosteronism. In response to a variety of stimuli, multiple bioactive molecules can activate TRPM7 and related signaling pathways, leading to fibroblast proliferation, differentiation and extracellular matrix production in cardiac fibroblasts. TRPM7-mediated Ca2+ signaling and TGF-β1 signaling pathways are critical for the formation of fibrosis. Accumulating evidence has demonstrated that TRPM7 is a potential pharmacological target for halting the development of fibrotic cardiac diseases. Reliable drug-like molecules for further development of high-affinity in vivo drugs targeting TRPM7 are urgently needed. The present review discusses the widespread and significant role of TRPM7 in cardiac fibrosis and focuses on its potential as a therapeutic target for alleviating heart fibrogenesis.
... It appears that TRPM7-mediated Ca 2+ signaling is essential for TGF-β1-induced fibroblast proliferation, differentiation, and the fibrogenesis cascade [37]. A role of TRPM7 in mediating the fibrogenesis cascade has also been observed in rat cardiac fibroblasts [193][194][195][196]. Moreover, TRPM7 is also suggested to be involved in fibrogenesis in rat sinus nodes [192], and in fibrosis induced by isoproterenol and oxidative stress [195]. ...
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.
... Moreover, rat cardiac fibroblasts incubated with angiotensin-II increased levels of protein expression of TRPM7, collagens I and III, which promoted fibrosis ( Zhou et al., 2015). In contrast, the downregulation of TRPM7 decreased its related current density and inhibited angiotensin-II mediated cardiac fibroblasts proliferation, differentiation, and collagen synthesis ( Li et al., 2017). Moreover, in rats with sick sinus syndrome, TRPM7 regulated angiotensin II-induced cardiac fibroblasts proliferation and collagen synthesis of sinoatrial node, involving Smad signaling pathway (Zhong et al., 2018b). ...
Calcium is an important second messenger required not only for the excitation-contraction coupling of the heart but also critical for the activation of cell signaling pathways involved in the adverse cardiac remodeling and consequently for the heart failure. Sustained neurohumoral activation, pressure-overload, or myocardial injury can cause pathologic hypertrophic growth of the heart followed by interstitial fibrosis. The consequent heart’s structural and molecular adaptation might elevate the risk of developing heart failure and malignant arrhythmia. Compelling evidences have demonstrated that Ca2+ entry through TRP channels might play pivotal roles in cardiac function and pathology. TRP proteins are classified into six subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), and TRPP (polycystin), which are activated by numerous physical and/or chemical stimuli. TRP channels participate to the handling of the intracellular Ca2+ concentration in cardiac myocytes and are mediators of different cardiovascular alterations. This review provides an overview of the current knowledge of TRP proteins implication in the pathologic process of some frequent cardiac diseases associated with the adverse cardiac remodeling such as cardiac hypertrophy, fibrosis, and conduction alteration.
... In addition, TRPM7 signaling appears to functionally interact with Ang II signaling. For example, Ang II stimulation upregulated TRPM7 expression in vascular smooth muscle cells [19], while TRPM7 regulated the downstream molecular phenotypes of CFs induced by Ang II [20]. In the clinic, TRPM and its mediated Ca 2+ -influx signal in CFs of SSS patients have been shown to play a key role in the transformation of CFs into CMFs [21], which was supported by the findings that TRPM7 contributed to the Ang II-mediated progression of atrial fibrosis through the regulation of influx of Ca 2+ and Mg 2+ [22]. ...
Sinoatrial node fibrosis is involved in the pathogenesis of sinus sick syndrome (SSS). Transient receptor potential (TRP) subfamily M member 7 (TRPM7) is implicated in cardiac fibrosis. However, the mechanisms underlying the regulation of sinoatrial node (SAN) fibrosis in SSS by TRPM7 remain unknown. The aim of this study was to investigate the role of angiotensin II (Ang II)/TRPM7/Smad pathway in the SAN fibrosis in rats with SSS. The rat SSS model was established with sodium hydroxide pinpoint pressing permeation. Forty-eight rats were randomly divided into six groups: normal control (ctrl), sham operation (sham), postoperative 1-, 2-, 3-, and 4-week SSS, respectively. The tissue explant culture method was used to culture cardiac fibroblasts (CFs) from rat SAN tissues. TRPM7 siRNA or encoding plasmids were used to knock down or overexpress TRPM7. Collagen (Col) distribution in SAN and atria was assessed using PASM–Masson staining. Ang II, Col I, and Col III levels in serum and tissues or in CFs were determined by ELISA. TRPM7, smad2 and p-smad2 levels were evaluated by real-time PCR, and/or western blot and immunohistochemistry. SAN and atria in rats of the SSS groups had more fibers and higher levels of Ang II, Col I and III than the sham rats. Similar findings were obtained for TRPM7 and pSmad2 expression. In vitro, Ang II promoted CFs collagen synthesis in a dose-dependent manner, and potentiated TRPM7 and p-Smad2 expression. TRPM7 depletion inhibited Ang II-induced p-Smad2 expression and collagen synthesis in CFs, whereas increased TRPM7 expression did the opposite. SAN fibrosis is regulated by the Ang II/TRPM7/Smad pathway in SSS, indicating that TRPM7 is a potential target for SAN fibrosis therapy in SSS.
The adult mammalian heart has negligible regenerative capacity and heals through formation of a collagen-based scar. Repair of the infarcted heart requires stimulation of an inflammatory reaction and subsequent activation of matrix-secreting myofibroblasts. Perturbed myofibroblast function results in defective healing and may cause rupture and adverse dilative remodeling, whereas prolonged, excessive, or unrestrained fibrogenic actions following infarction may be associated with progression of fibrosis and development of heart failure. Mechanosensitive pathways are critically implicated in regulation of the cellular responses involved in repair, fibrosis, and adverse remodeling of the infarcted heart. In this chapter, we review the role of mechanical stress-mediated signals in scar formation and in fibrotic remodeling of the infarcted heart. Mechanosensitive signaling plays a critical role in stimulation of neurohumoral cascades, and in activation of growth factors in the infarcted heart, and is implicated, along with the release of biochemical mediators, in myofibroblast conversion and activation. In cardiac fibroblasts, integrin-mediated signals and mechanosensitive ion channels transduce stress-induced signaling cascades that activate matrix-synthetic programs. Interventions targeting mechanically stimulated cascades may hold promise as therapeutic strategies against adverse post-infarction remodeling.
