Transcriptional signatures regulated by TRPC1/C4-mediated Background Ca2+ entry after pressure-overload induced cardiac remodelling

https://doi.org/10.1016/j.pbiomolbio.2020.07.006Get rights and content

Abstract

Aims

After summarizing current concepts for the role of TRPC cation channels in cardiac cells and in processes triggered by mechanical stimuli arising e.g. during pressure overload, we analysed the role of TRPC1 and TRPC4 for background Ca2+ entry (BGCE) and for cardiac pressure overload induced transcriptional remodelling.

Methods and results

Mn2+-quench analysis in cardiomyocytes from several Trpc-deficient mice revealed that both TRPC1 and TRPC4 are required for BGCE. Electrically-evoked cell shortening of cardiomyocytes from TRPC1/C4-DKO mice was reduced, whereas parameters of cardiac contractility and relaxation assessed in vivo were unaltered. As pathological cardiac remodelling in mice depends on their genetic background, and the development of cardiac remodelling was found to be reduced in TRPC1/C4-DKO mice on a mixed genetic background, we studied TRPC1/C4-DKO mice on a C57BL6/N genetic background. Cardiac hypertrophy was reduced in those mice after chronic isoproterenol infusion (−51.4%) or after one week of transverse aortic constriction (TAC; −73.0%). This last manoeuvre was preceded by changes in the pressure overload induced transcriptional program as analysed by RNA sequencing. Genes encoding specific collagens, the Mef2 target myomaxin and the gene encoding the mechanosensitive channel Piezo2 were up-regulated after TAC in wild type but not in TRPC1/C4-DKO hearts.

Conclusions

Deletion of the TRPC1 and TRPC4 channel proteins protects against development of pathological cardiac hypertrophy independently of the genetic background. To determine if the TRPC1/C4-dependent changes in the pressure overload induced alterations in the transcriptional program causally contribute to cardio-protection needs to be elaborated in future studies.

Introduction

Pathological cardiac remodelling develops during conditions where the cardiovascular system is subjected to increasing mechanical forces provoked by vasoactive neurohumoral agents like angiotensin II (AngII) or by physical changes observed during pressure overload conditions such as aortic valve stenosis or hypertension associated with elevated peripheral vascular resistance. These conditions evoke pathological cardiac remodelling processes including exaggerated neurohumoral stimulation, abnormal Ca2+ signalling in cardiomyocytes, cardiomyocyte growth, fibrosis and complex transcriptional changes associated to guaranteeing cardiac function.

TRP proteins have been revealed in the last years as constituents of cation channels in multiple cells of the cardiovascular system and as determinants of cardiovascular functions. They were already described in cardiac cells 20 years ago (Freichel et al., 1999). In mammals, 28 TRP proteins are found and are grouped into six families depending on structural homology: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), and TRPP (polycystin). TRP proteins form Na+ and Ca2+ conducting channels that are activated by different physical (e.g. mechanical stretch) and/or chemical stimuli (e.g. agonists including neurotransmitters or hormones). They can contribute to Ca2+ homeostasis by either directly conducting Ca2+ or indirectly regulating Ca2+ entry by membrane depolarization and modulation of voltage-gated Ca2+ channels (Flockerzi and Nilius, 2014; Freichel et al., 2014; Wu et al., 2010a).

The involvement of TRP channels as mechanosensors or mediators of mechanical stimuli, including osmomechanical stimulation, has been the topic of several reviews (Christensen and Corey, 2007; Eijkelkamp et al., 2013; Lin and Corey, 2005; Sharif-Naeini et al., 2008). Within the entire superfamily of TRP channels, several members of the TRPC family have been proposed as mechanosensitive channels. It was shown that TRPC1 is a component of mechanosensitive cation channels in frog oocytes heterologously expressing human Trpc1 cDNA (Maroto et al., 2005). In addition, TRPC6 was also reported as a sensor of mechanically and osmotically induced membrane stretch in HEK-293 and in CHO cells following heterologous expression of the mouse Trpc6 cDNA (Spassova et al., 2006). However, discrepancies attributed to the expression in heterologous systems have been described regarding the mechanosensitivity of both TRPC1 and TRPC6 (Gottlieb et al., 2008). Another study revealed that the cellular environment, in which these TRPCs are expressed, is fundamental to confer the mechanic dependence of these channels. Quick et al. (2012) showed that TRPC6 expression leads to a potentiation of TRPC3-mediated mechanically evoked currents in ND-C cells but not in HEK293 or CHO K1 cells; moreover, using TRPC3/C6-deficient mice the authors revealed that TRPC3 and TRPC6 are required for the normal function of cells involved in touch and hearing, and are potential components of mechanotransducing complexes (Quick et al., 2012). Further analysis using TRPC-deficient mice showed that the stretch-induced nuclear translocation of the transcription factor Zyxin in endothelial cells of femoral arteries depends on the presence of TRPC3 but not TRPC6 (Suresh Babu et al., 2012), and that TRPC5 channels are involved in the mechanical sensor in aortic baroreceptors (Lau et al., 2016). From the studies analysing mechanosensitive channels or cell functions in TRPC-deficient cells or organs it cannot be concluded that the corresponding TRPC isoform forms a mechanosensing channel itself. Alternatively they could operate downstream of the proper mechanosensor which is not part of the channel complex but is functionally linked to the corresponding TRPC channels e.g. by communication through a secondary signal (Christensen and Corey, 2007). Indeed, Mederos y Schnitzler et al. (2008) showed that membrane stretch does not primarily gate TRPC6 ion channels, but leads to agonist-independent activation of Gq/11-coupled receptors such as AT1-AngII receptors, which subsequently signal to TRPC channels in a G protein- and phospholipase C (PLC)-dependent manner (Mederos y Schnitzler et al., 2008). PLC-mediated generation of diacylglycerol (DAG) can activate TRPC2 (Lucas et al., 2003) TRPC3, TRPC6 (Hofmann et al., 1999) and TRPC7 (Beck et al., 2006). For activation of TRPC4 or TRPC5, DAG is not sufficient, but DAG-mediated activation can contribute to the activation of these TRPC isoforms. Indirect activation of TRPC4 and TRPC5 was demonstrated, if – concomitant to DAG generation - the levels of phosphatidylinositol 4, 5-bisphosphate (PIP2), which inhibits channels formed by TRPC4 or TRPC5, are depleted as it may occur by mechanical activation of Gq/11-coupled receptors and PLC (Otsuguro et al., 2008; Storch et al., 2017; Tsvilovskyy et al., 2009).

In the heart it has been proposed that TRP proteins, including TRPC, are mediators of several physiological and pathophysiological cardiovascular processes (Abramowitz and Birnbaumer, 2009; Dietrich et al., 2007a, 2010; Hof et al., 2019; Inoue et al., 2006; Vennekens, 2011; Watanabe et al., 2009). Numerous efforts have been made to establish the role of members of this cation channel family in the development of cardiac remodelling (Eder and Molkentin, 2011; Guinamard and Bois, 2007; Nishida and Kurose, 2008). The knowledge regarding the functional role of TRP channels for Ca2+ homeostasis in cardiomyocytes and cardiac fibroblasts, their contribution to cardiac contractility and conduction as well as for the development of arrhythmias and pathological remodelling processes has been summarized recently by others and by us (Falcon et al., 2019, 2020; Freichel et al., 2017; Hof et al., 2019; Inoue et al., 2012; Numata et al., 2016; Yue et al., 2015). All seven TRPC channels are reported to be expressed in the mammalian heart; their expression has been reported under normal conditions as well as to be differentially expressed in cells and tissues from experimental models inducing cardiac remodelling or in myocardial biopsies from diseased human hearts (Freichel et al., 2017). The heart is composed of several cell types including cardiomyocytes and cardiac fibroblasts, which represent the most abundant cardiac cell type in numbers. Cardiac fibroblasts are important in controlling the local environment of cardiomyocytes through paracrine signalling and by cell-to-cell interactions. As such, cardiac fibroblasts are critical regulators of the development of cardiac remodelling and arrhythmias (Baudino et al., 2006; Kakkar and Lee, 2010; Souders et al., 2009). In addition to cardiomyocyte, expression of TRPC channels in cardiac fibroblasts has been reported as well as its putative function (Freichel et al., 2017). C-type natriuretic peptide-induced cation currents with characteristics of TRPC-mediated currents were reported in rat cardiac fibroblasts (Rose et al., 2007). Using TRPC-KO mice and/or pharmacological approaches the role of TRPC channels in cardiac fibroblasts, myofibroblast differentiation and/or cardiac fibrosis regulation has been postulated (Camacho Londoño et al., 2015; Davis et al., 2012; Harada et al., 2012; Harikrishnan et al., 2019; Ikeda et al., 2013; Kapur et al., 2014; Kitajima et al., 2016; Lin et al., 2019; Nishida et al., 2007; Saliba et al., 2019). However, the functional role of TRPCs in cardiac fibroblasts is still poorly understood, and TRPCs are dispensable for acute receptor-operated Ca2+ entry (ROCE) evoked by AngII stimulation as this type of ROCE is unaltered in cardiac fibroblasts lacking all TRPC subtypes (Camacho Londoño et al., 2020).

In efforts to identify the activity of TRPC channels in cardiomyocytes different approaches have been used and described in recent reviews (Ahmad et al., 2017; Falcon et al., 2019; Freichel et al., 2017). Using antibodies against TRPC1, TRPC3 or TRPC6 in atrial or ventricular myocytes, the attribution of currents or Ca2+ signals to member of the TRPC family was reported (Alvarez et al., 2008; Fauconnier et al., 2007; Kojima et al., 2010; Mohl et al., 2011; Zhang et al., 2013); in addition, using a similar approach the contribution of those three proteins to the store operated Ca2+ entry (SOCE) in ventricular myocytes was postulated (Wen et al., 2018). Interestingly, in mouse ventricular cardiomyocytes, a stretch-induced non-selective cation conductance was sensitive to antibodies against TRPC6 (Dyachenko et al., 2009). Other approaches used to investigate TRPCs in cardiomyocytes are those altering the TRPC expression in cardiomyocytes (Overexpression or knock-down by e.g. siRNA or by expression of dominant-negative variants). Taking advantage of such approaches it was postulated that TRPC1, TRPC3, TRPC4, TRPC5 or TRPC6 in Neonatal Rat Ventricular Myocytes (NRVM) or adult cardiomyocytes are part of the SOCE and/or ROCE induced by agents like AngII, Endothelin-1 or aldosterone (Kinoshita et al., 2010; Nakayama et al., 2006; Onohara et al., 2006; Sabourin et al., 2016). In addition, it was shown that the SOCE mediated by TRPC3 was diminished in adult cardiomyocytes (mouse or cat) expressing dominant-negative variants of TRPC4 (dnTRPC4) or TRPC6 (TRPC6dn) (Makarewich et al., 2014; Wu et al., 2010b) suggesting functional interaction of the TRPC1/C4/C5 and TRPC3/C6/C7 subgroups. Moreover, dnTRPC4, dnTRPC3 or TRPC6dn were able to reduce the increased SOCE observed in cardiomyocytes from mice challenged with pressure overload via transverse aortic constriction (TAC) (Wu et al., 2010b). dnTRPC3 expression also reduced Ca2+ entry evoked upon PLC stimulation and mediated by the sodium/calcium exchanger (NCX) in adult rat cardiomyocytes (Eder et al., 2007). TRPC3-like currents were evoked in stem cell-derived mouse cardiomyocytes (mESC-CMs) by OAG (1-Oleoyl-2-acetyl-sn-glycerol) and these currents were reduced by the TRPC3 blocker Pyr3 or by a TRPC3-dominant negative variant of TRPC3, which additionally decreased the pacemaker activity of the cells (Qi et al., 2016); however, Pyr3 specificity was tested showing effects on other Ca2+ channels like Orai1 (Schleifer et al., 2012). In NRVM it was proposed that TRPC7 proteins could mediate AngII-induced when TRPC7 is overexpressed (Satoh et al., 2007).

A rigorous approach to study the role of TRPC in cardiac cells is using cardiomyocytes isolated from TRPC-deficient mice. With this approach it was reported in cells from TRPC3/C6-deficient mice that the peak of AngII-induced Ca2+ transients and AngII-evoked L-type currents were abolished (Klaiber et al., 2011). Others reported in TRPC6-deficient cardiomyocytes the absence of a TRPC-like current observed in myocytes from wild type mice that chronically received isoproterenol (Iso) and were acutely stimulated by Endothelin-1 (Xie et al., 2012). In adult cardiomyocytes a pressure overload-induced non selective whole cell current was attributed to TRPC1; additionally, in the same report and using neonatal cardiomyocytes from TRPC1-KO mice it was determined that TRPC1 influences the stretch activated gene program (ANP and BNP), which was also sensitive to the AngII-receptor (AT1) blocker losartan (Seth et al., 2009). In human pluripotent stem-cell derived cardiomyocytes, where Trpc1 was genetically deleted by CRISPR/Cas9 technology, cellular hypertrophy was significantly attenuated (Tang et al., 2019). Finally, we identified in a systematic analysis of multiple knock-out mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn2+-quench microfluorimetry, a background Ca2+ entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not TRPC3/C6. This BGCE in TRPC1/C4-deficient murine cardiomyocytes lowers diastolic and systolic Ca2+ concentrations under steady state pacing conditions and under neurohumoral stimulation (Iso or AngII) (Camacho Londoño et al., 2015); however, the contribution of either TRPC1 or TRPC4 alone was not described.

Supported by the influence of Ca2+ signalling on cardiomyocyte function a role of TRPC1, TRPC3, TRPC4 and TRPC6 proteins in signalling cascades mediating the development of cardiac hypertrophy and remodelling has been proposed. Primary experimental evidence supporting this hypothesis has been based on cellular experiments in NRVMs followed by experiments in cardiomyocytes from transgenic mice over-expressing either TRPC proteins or dominant negative isoforms of them in the heart, or by using TRPC-putative blockers (Brenner and Dolmetsch, 2007; Bush et al., 2006; Cooley et al., 2014; Kiyonaka et al., 2009; Koitabashi et al., 2010; Kuwahara et al., 2006; Li et al., 2015; Nakamura et al., 2015; Nishida et al., 2007, 2010; Ohba et al., 2006, 2007; Seo et al., 2014; Vindis et al., 2010).

Similar approaches to those used for the analysis of isolated cells by altering the expression of TRPC-proteins, or by genetic or pharmacological inhibition of TRPCs have been used to determine its role in the heart and in the cardiovascular system. Models of heart disease including neurohumoral stimulation or pressure overload, which mimic for example altered catecholamine/β-adrenergic levels during heart disease (Hartupee and Mann, 2017; Hasenfuss, 1998; Lefkowitz et al., 2000) have been combined with TRPC in vivo models. Representative works on this field are briefly mentioned below. Overexpression of TRPC3 proteins under control of the cardiomyocyte specific α-MHC promoter in mice leads to cardiac hypertrophy, increased AngII/Phenylephrine (PE)- and TAC-induced hypertrophy, and heart failure after two weeks of TAC (Nakayama et al., 2006). To that respect, it was reported that Pyr3 attenuated TAC-induced hypertrophy in mice (Kiyonaka et al., 2009); nevertheless, Pyr3 also blocks Orai1 channels (Schleifer et al., 2012) and Orai1 genetic or pharmacological inhibition preserves left ventricular systolic function after TAC (Bartoli et al., 2020). Another group investigated the effect of TRPC6 overexpression in mouse cardiomyocytes. High TRPC6 expression in cardiomyocytes provoked death between 5 and 12 days after birth, possibly due to severe cardiomyopathy; transgenic mice with intermediate TRPC6 expression levels developed cardiomegaly and congestive heart failure around 30 weeks of age; mice with lower expression levels had no obvious defect, but they showed a significant higher response to TAC (Kuwahara et al., 2006).

Cardiomyocytes from hypertrophied hearts after TAC showed increased Ca2+ influx or a non-selective current associated with TRPC channels that is not mediated by L-type Ca2+ channels or the Na+/Ca2+ exchanger (Seth et al., 2009; Wu et al., 2010b). The first work pointed to TRPC1 channels as mediators of this current because it was absent in cardiomyocytes from TRPC1-deficient mice. Furthermore, TRPC1-deficient mice had reduced TAC- and AngII-induced hypertrophy responses (Seth et al., 2009). The second work attributed the increased Ca2+ entry in hypertrophied cardiomyocytes to SOCE mechanisms. Transgenic mice with cardiomyocyte expression of dominant-negative constructs of either TRPC3, TRPC4 or TRPC6 developed reduced pathological hypertrophy induced by TAC or AngII/PE infusion (Wu et al., 2010b). Similarly, expression of a dominant-negative TRPC4 in cardiomyocytes reduced cardiac hypertrophy and remodelling after myocardial infarction (Makarewich et al., 2014).

The above mentioned BGCE mediated by TRPC1/C4 is also relevant for the development of pathological cardiac remodelling. Neurohumoral-induced cardiac hypertrophy evoked by chronic infusion of isoproterenol or AngII was reduced in TRPC1/C4-DKO but not in TRPC1- or TRPC4- single deficient mice. Pressure overload-induced hypertrophy (TAC), interstitial fibrosis as well as deterioration of cardiac function were all ameliorated in TRPC1/C4-DKO mice on a mixed C57Bl6/N and 129SvJ background (Camacho Londoño et al., 2015). In the same study it was shown that TRPC3/C6-DKO mice (C57BL6/N or mixed genetic background) were not protected from the development of AngII-, Iso- or TAC-induced cardiac hypertrophy. Similarly, another group also observed no protection in TRPC3/C6-DKO mice after AngII treatment, but a reduction of the hypertrophy response in TRPC3- but not in TRPC6-single deficient mice (Domes et al., 2015). TRPC3-KO mice were protected from both AngII- and PE-induced hypertrophy as well as from deterioration of cardiac function, which was associated to a reduced Cav1.2 expression in TRPC3-KO mice (Han et al., 2016). However, TRPC3-DKO mice were not protected from TAC-induced hypertrophy despite the reduction in cardiac fibrosis and the proposed regulation of reactive oxygen species by TRPC3 under this model (Kitajima et al., 2016; Numaga-Tomita et al., 2016). In a canine model of atrial fibrillation Pyr3 suppressed atrial fibrillation while decreased fibroblast proliferation and extracellular matrix gene expression (Harada et al., 2012). In TRPC6-deficient mice the Iso-induced increase in cardiac mass gain was reported to be reduced (Xie et al., 2012). Nonetheless, and different to other reports, TRPC3/C6-DKO mice under a C57Bl/6J genetic background, but not the single TRPC3-KO or TRPC6-KO, were protected from pressure overload-induced cardiac hypertrophy (Seo et al., 2014). Beyond that, TRPC6 was also reported to be important in scar formation after myocardial infarction which was reduced in TRPC6-deficient mice (Davis et al., 2012). Recently it was shown that in vivo inhibition of TRPC6 by BI-749327 was able to reduce the cardiac fibrosis produced by pressure overload as well as the fibrosis developed in a model of renal injury (Lin et al., 2019).

Differences between TRPC-KO mouse lines with different genetic background could account for the discrepancies reported between different studies mentioned above. The genetic background influences the outcome in models of cardiovascular disease (Kiper et al., 2013; Waters et al., 2013). Our previous report (Camacho Londoño et al., 2015) about the impact of the TRPC1/C4-mediated BGCE on cardiac remodelling was done mainly with mice from the first generation (F1) between TRPC1/C4-DKO (129SvJ) and TRPC1/C4-DKO (C57BL6N). Therefore, and to further analyse the effect of complete inactivation of TRPC1/C4 for cardiac remodelling in the adult heart of mice with an independent commonly used genetic background we generated a TRPC1/C4 deficient mouse line with a defined C57BL6/N background. Consequently, we investigated in this report the causal involvement of TRPC1/C4-DKO (C57BL6/N) respect to the Iso- and pressure overload-induced cardiac hypertrophy and we extended our analysis to the gene expression profile after TAC in the absence of TRPC1 and TRPC4 proteins. Using Mn2+-quench microfluorimetry on isolated adult mouse cardiomyocytes, neurohumoral- and pressure overload-induced cardiac remodelling and expression analysis we concluded that TRPC1/C4 genetic inactivation: I) Reduces BGCE, II) protects against development of pathological cardiac hypertrophy independently of the genetic background and III) is associated with specific changes in transcriptional response evoked by pressure overload. These transcriptional changes need to be investigated in depth in further analysis.

Section snippets

Materials and methods

2.1. Animal Experiments. All animal experiments were approved and performed according to the regulations of the Regional Council of Karlsruhe and the University of Heidelberg (AZ 35–9185.81/G-199/12; AZ 35–9185.81/G131/15) and the University of Saarland (AZ K110/180–07) conform to the guidelines from Directive (2010)/63/EU of the European Parliament on the protection of animals used for scientific purposes. Mice were maintained under specified pathogen-free conditions at the animal facility

Background Ca2+ entry (BGCE) in cardiomyocytes required both TRPC1 and TRPC4 proteins, which regulate the contractility of isolated cardiomyocytes

We have previously shown that cardiomyocytes isolated from TRPC1/C4-DKO(F1) exhibit a reduced BGCE under basal conditions and after chronic in vivo neurohumoral application of isoproterenol (Iso) or angiotensin II (AngII) (Camacho Londoño et al., 2015). In this study, we now tested the role of TRPC1 and TRPC4 for BGCE under acute stimulation with Iso or AngII. In line with the results obtained after chronic neurohumoral stimulation we observed that cardiomyocytes from TRPC1/C4-DKO(F1) mice have

Discussion

During pathological cardiac remodelling triggered by combined neurohumoral and mechanical stimuli, the heart responds by developing myocyte hypertrophy, depositing fibrotic tissue, activating inflammatory pathways, among others, to ensure cardiac function. Behind these cardiac responses to stress the activation of Ca2+-depending pathways and changes in transcription patterns are important mechanisms that require analysis to understand disease progression. We described a background Ca2+-entry

Conclusions

Together, our results indicate that TRPC1 and TRPC4 proteins mediate a BGCE in adult cardiomyocytes and operate as a crucial mediator for neurohumoral- and pressure overload-induced cardiac hypertrophy as well are associated with changes in the expression of specific genes during the development of pathological cardiac remodelling. Whether the TRPC1/C4- and BGCE-dependent changes in the pressure overload induced alterations in the transcriptional program in the heart causally contribute to

Funding

This research was funded by the DZHK (German Centre for Cardiovascular Research), the BMBF (German Ministry of Education and Research); the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): Project-ID 239283807 – TRR 152, FOR 2289, the Collaborative Research Center (SFB) 1118, GRK1326 and the DIAMICOM graduate school (GRK, 1874), and the Intramural Research Program of the NIH (Project Z01-ES-101684 to LB).

CRediT authorship contribution statement

Juan E. Camacho Londoño: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing. Vladimir Kuryshev: Formal analysis, Methodology, Visualization, Writing - review & editing. Markus Zorn: Writing - review & editing. Kathrin Saar: Writing - review & editing. Qinghai Tian: Writing - review & editing, Formal analysis. Norbert Hübner: Writing - review & editing. Peter

Acknowledgment

We are thankful to Manuela Ritzal, Hans-Peter Gensheimer, Stefanie Buchholz, Martin Simon Thomas, Anne Vecerdea, Tanja Volz, Sabrina Hennig and the team from the Interfakultäre Biomedizinische Forschungseinrichtung (IBF) from the Heidelberg University for expert technical assistance. We thank the nCounter Core Facility Heidelberg for providing the nCounter system and related services, Dr. Sebastian Uhl for his assistance with the isolated atria experiments and Dr. Ulrich Kriebs with his

References (125)

  • A.G. Nickel et al.

    Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure

    Cell Metabol.

    (2015)
  • M. Nishida et al.

    Galpha12/13-mediated up-regulation of TRPC6 negatively regulates endothelin-1-induced cardiac myofibroblast formation and collagen synthesis through nuclear factor of activated T cells activation

    J. Biol. Chem.

    (2007)
  • M. Nishida et al.

    Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition

    J. Biol. Chem.

    (2010)
  • T. Ohba et al.

    Upregulation of TRPC1 in the development of cardiac hypertrophy

    J. Mol. Cell. Cardiol.

    (2007)
  • Z. Qi et al.

    TRPC3 regulates the automaticity of embryonic stem cell-derived cardiomyocytes

    Int. J. Cardiol.

    (2016)
  • S. Andrews

    FastQC: a quality control tool for high throughput sequence data

  • J. Abramowitz et al.

    Physiology and pathophysiology of canonical transient receptor potential channels

    Faseb. J.

    (2009)
  • J. Alvarez et al.

    ATP/UTP activate cation-permeable channels with TRPC3/7 properties in rat cardiomyocytes

    Am. J. Physiol. Heart Circ. Physiol.

    (2008)
  • F. Bartoli et al.

    Orai1 channel inhibition preserves left ventricular systolic function and normal Ca(2+) handling after pressure overload

    Circulation

    (2020)
  • T.A. Baudino et al.

    Cardiac fibroblasts: friend or foe?

    Am. J. Physiol. Heart Circ. Physiol.

    (2006)
  • B. Beck et al.

    TRPC7 is a receptor-operated DAG-activated channel in human keratinocytes

    J. Invest. Dermatol.

    (2006)
  • D.J. Beech et al.

    Force sensing by piezo channels in cardiovascular health and disease

    Arterioscler. Thromb. Vasc. Biol.

    (2019)
  • J.S. Brenner et al.

    TrpC3 regulates hypertrophy-associated gene expression without affecting myocyte beating or cell size

    PloS One

    (2007)
  • J.E. Camacho Londoño et al.

    Angiotensin-II-evoked Ca2+ entry in murine cardiac fibroblasts does not depend on TRPC channels cells

    (2020)
  • J.E. Camacho Londoño et al.

    A background Ca2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling

    Eur. Heart J.

    (2015)
  • E.Y. Chen et al.

    Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool

    BMC Bioinf.

    (2013)
  • A.P. Christensen et al.

    TRP channels in mechanosensation: direct or indirect activation?

    Nat. Rev. Neurosci.

    (2007)
  • N. Cooley et al.

    The phosphatidylinositol(4,5)bisphosphate-binding sequence of transient receptor potential channel canonical 4alpha is critical for its contribution to cardiomyocyte hypertrophy

    Mol. Pharmacol.

    (2014)
  • A. Dietrich et al.

    TRPC channels in vascular cell function

    Thromb. Haemostasis

    (2010)
  • A. Dietrich et al.

    Pressure-induced and store-operated cation influx in vascular smooth muscle cells is independent of TRPC1

    Pflügers Archiv

    (2007)
  • A. Dietrich et al.

    Increased vascular smooth muscle contractility in TRPC6-/- mice

    Mol. Cell Biol.

    (2005)
  • A. Dobin et al.

    STAR: ultrafast universal RNA-seq aligner

    Bioinformatics

    (2013)
  • K. Domes et al.

    Murine cardiac growth, TRPC channels, and cGMP kinase I

    Pflügers Archiv

    (2015)
  • P. Eder

    Cardiac remodeling and disease: SOCE and TRPC signaling in cardiac pathology

    Adv. Exp. Med. Biol.

    (2017)
  • P. Eder et al.

    TRPC channels as effectors of cardiac hypertrophy

    Circ. Res.

    (2011)
  • P. Eder et al.

    Phospholipase C-dependent control of cardiac calcium homeostasis involves a TRPC3-NCX1 signaling complex

    Cardiovasc. Res.

    (2007)
  • N. Eijkelkamp et al.

    Transient receptor potential channels and mechanosensation

    Annu. Rev. Neurosci.

    (2013)
  • D. Falcon et al.

    TRP channels: current perspectives in the adverse cardiac remodeling

    Front. Physiol.

    (2019)
  • D. Falcon et al.

    TRPC channels: dysregulation and Ca(2+) mishandling in ischemic heart disease

    Cells

    (2020)
  • L.K. Farmer et al.

    TRPC6 binds to and activates calpain, independent of its channel activity, and regulates podocyte cytoskeleton, cell adhesion, and motility

    J. Am. Soc. Nephrol.

    (2019)
  • J. Fauconnier et al.

    Insulin potentiates TRPC3-mediated cation currents in normal but not in insulin-resistant mouse cardiomyocytes

    Cardiovasc. Res.

    (2007)
  • V. Flockerzi et al.

    TRPs: truly remarkable proteins

    Handb. Exp. Pharmacol.

    (2014)
  • M. Freichel et al.

    TRP channels in the heart

  • M. Freichel et al.

    Store-operated cation channels in the heart and cells of the cardiovascular system

    Cell. Physiol. Biochem.

    (1999)
  • M. Freichel et al.

    Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4-/- mice

    Nat. Cell Biol.

    (2001)
  • M. Freichel et al.

    TRPC4- and TRPC4-containing channels

    Handb. Exp. Pharmacol.

    (2014)
  • P. Gottlieb et al.

    Revisiting TRPC1 and TRPC6 mechanosensitivity

    Pflügers Archiv

    (2008)
  • R. Guinamard et al.

    Involvement of transient receptor potential proteins in cardiac hypertrophy

    Biochim. Biophys. Acta

    (2007)
  • J.W. Han et al.

    Resistance to pathologic cardiac hypertrophy and reduced expression of CaV1.2 in Trpc3-depleted mice

    Mol. Cell. Biochem.

    (2016)
  • M. Harada et al.

    Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation

    Circulation

    (2012)
  • Cited by (0)

    View full text