Role of the TRPM4 Channel in Cardiovascular Physiology and Pathophysiology

Wang, Chen; Naruse, Keiji; Takahashi, Katsuroku

doi:10.3390/cells7060062

Cited by 41 publications

(41 citation statements)

References 143 publications

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“…Prime candidates for mediating this mechanism are mechanosensitive ion channels. In cardiac mechano-transduction, where mechanical stimuli are converted into electrical or chemical signals (28,29), Ca 2+ -dependent ion channels, such as transient receptor potential (TRP) channels (16), act as important modulators of intracellular Ca 2+ homeostasis (30) and are thought to be unique biosensors that activate specific pathological LVH signalling pathways (31,32). As a Ca 2+ -and voltage-activated non-selective monovalent cation channel, transient receptor potential cation channel subfamily melastatin 4 (TRPM4) may contribute to an increase in intracellular Ca 2+ concentration by causing membrane depolarization (33), although we and others (40,41,42) have demonstrated that mammalian TRP channels, including TRPM4, are not directly stretch-activated.…”

Section: Introductionmentioning

confidence: 99%

The Ca²⁺-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

Guo

et al. 2020

Preprint

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Pathological left ventricular hypertrophy (LVH) is a consequence of pressure overload caused by systemic hypertension or aortic stenosis and is a strong predictor of cardiac failure and mortality. Understanding the molecular pathways in the development of pathological LVH may lead to more effective treatment. Here, we show that the transient receptor potential cation channel subfamily melastatin 4 (TRPM4) ion channel is an important contributor to the mechanosensory transduction of pressure overload that induces LVH. In mice with pressure overload induced by transverse aortic constriction (TAC) for two weeks, cardiomyocyte TRPM4 expression was reduced, as compared to control mice. Cardiomyocyte-specific TRPM4 inactivation reduced by ~50% the degree of TAC-induced LVH, as compared with wild type (WT). In WT mice, TAC activated the CaMKIIδ-HDAC4-MEF2A but not the calcineurin-NFAT-GATA4 pathway. In TRPM4 knock-out mice, activation of the CaMKIIδ-HDAC4-MEF2A pathway by TAC was significantly reduced. However, consistent with a reduction in the known inhibitory effect of CaMKIIδ on calcineurin activity, reduction in the CaMKIIδ-HDAC4-MEF2A pathway was associated with partial activation of the calcineurin-NFAT-GATA4 pathway. These findings indicate that the TRPM4 channel and its cognate signalling pathway are potential novel therapeutic targets for the prevention of pathological pressure overload-induced LVH.Significance statementPathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. Preventing pressure overload LVH is a major goal of therapeutic intervention. Current treatments aim to remove the stimulus for LVH by lowering elevated blood pressure or replacing a stenotic aortic valve. However, neither of these interventions completely reverses adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling, remains unresolved. Here, we demonstrate that the TRPM4 channel is a component of the mechanosensory transduction pathway that ultimately leads to LVH.

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Section: Introductionmentioning

confidence: 99%

The Ca²⁺-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

Guo

et al. 2020

Preprint

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“…Nevertheless, future studies to discern possible mechanisms and to determine the level and other partners in the Trpm4-Na V 1.5 interactions are warranted. The importance of TRPM4 in cardiac electrical activity is highlighted by mutations in its gene linked to conduction disorders such as right bundle branch block, Brugada syndrome, and atrio-ventricular block [24,40].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have proposed the hypothesis that TRPM4 may functionally affect the activity of other cardiac ion channels, such as the main cardiac voltage-gated Na + channel Na V 1.5 [12,24]. Since TRPM4 carries an inward current close to resting membrane potential and an outward current at depolarized potentials, increasing or decreasing TRPM4 expression may critically influence the availability of Na V 1.5 channels.…”

Section: Deletion Of Trpm4 Alters the Function And Expression Of Na Vmentioning

confidence: 99%

Deletion ofTrpm4alters the function and expression of Na_V1.5 channel in murine cardiac myocytes

Ozhathil

Rougier

Arullampalam

et al. 2020

Preprint

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AbstractTransient receptor potential melastatin member 4 (TRPM4) encodes a Ca+ -activated non-selective cation channel that is functionally expressed in several tissues including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases including conduction block and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized. To study the functional consequences of Trpm4 deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunohistochemistry studies on isolated atrial and ventricular cardiac myocytes and surface, pseudo and intracardiac ECGs either in vivo or on Langendorff-perfused explanted mouse hearts. We observed that Trpm4 is expressed in atrial and ventricular cardiac myocytes and that deletion of Trpm4 unexpectedly reduces the peak Na+ currents in the myocytes. Hearts from Trpm4-/- mice presented increased sensitivity towards mexiletine, a Na+ channel blocker, and slower intraventricular conduction, consistent with the reduction of peak Na+ current observed in the isolated cardiac myocytes. This reduction in Na+ current is explained by the observed decrease in protein expression of NaV1.5 in Trpm4-/- mice. This study suggests that Trpm4 expression impacts Na+ current in murine cardiac myocytes and points towards a novel function of Trpm4 regulating the NaV1.5 expression in murine cardiac myocytes.

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“…Therefore, TRPM4 may provide a better option to therapeutically target Ca 2+ mishandling. Interestingly, despite the upregulation of TRPM4 in failing human hearts, the channel itself is impermeable to Ca 2+ ; however, it is both Ca 2+ - and voltage-activated ( Nilius et al, 2003 , 2005 ; Wang et al, 2018 ). TRMP4 expression is upregulated by 50-fold in spontaneously hypertensive rats when compared to controls ( Guinamard et al, 2006 ).…”

Section: Calcium Handling Proteins In Cardiac Hypertrophy and Hf Andmentioning

confidence: 99%

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

2020

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Diseases of the heart, such as heart failure and cardiac arrhythmias, are a growing socioeconomic burden. Calcium (Ca 2+) dysregulation is key hallmark of the failing myocardium and has long been touted as a potential therapeutic target in the treatment of a variety of cardiovascular diseases (CVD). In the heart, Ca 2+ is essential for maintaining normal cardiac function through the generation of the cardiac action potential and its involvement in excitation contraction coupling. As such, the proteins which regulate Ca 2+ cycling and signaling play a vital role in maintaining Ca 2+ homeostasis. Changes to the expression levels and function of Ca 2+-channels, pumps and associated intracellular handling proteins contribute to altered Ca 2+ homeostasis in CVD. The remodeling of Ca 2+-handling proteins therefore results in impaired Ca 2+ cycling, Ca 2+ leak from the sarcoplasmic reticulum and reduced Ca 2+ clearance, all of which contributes to increased intracellular Ca 2+. Currently, approved treatments for targeting Ca 2+ handling dysfunction in CVD are focused on Ca 2+ channel blockers. However, whilst Ca 2+ channel blockers have been successful in the treatment of some arrhythmic disorders, they are not universally prescribed to heart failure patients owing to their ability to depress cardiac function. Despite the progress in CVD treatments, there remains a clear need for novel therapeutic approaches which are able to reverse pathophysiology associated with heart failure and arrhythmias. Given that heart failure and cardiac arrhythmias are closely associated with altered Ca 2+ homeostasis, this review will address the molecular changes to proteins associated with both Ca 2+handling and-signaling; their potential as novel therapeutic targets will be discussed in the context of pre-clinical and, where available, clinical data.

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Role of the TRPM4 Channel in Cardiovascular Physiology and Pathophysiology

Cited by 41 publications

References 143 publications

The Ca²⁺-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

The Ca²⁺-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

Deletion ofTrpm4alters the function and expression of Na_V1.5 channel in murine cardiac myocytes

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

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Role of the TRPM4 Channel in Cardiovascular Physiology and Pathophysiology

Cited by 41 publications

References 143 publications

The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

Deletion ofTrpm4alters the function and expression of NaV1.5 channel in murine cardiac myocytes

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

Contact Info

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The Ca²⁺-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

The Ca²⁺-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

Deletion ofTrpm4alters the function and expression of Na_V1.5 channel in murine cardiac myocytes