TRPM4 Modulates Right Ventricular Remodeling Under Pressure Load Accompanied With Decreased Expression Level

Frede, W.; Medert, Rebekka; Poth, Tanja; Gorenflo, Matthias; Vennekens, Rudi; Freichel, Marc; Uhl, Sebastian

doi:10.1016/j.cardfail.2020.02.006

Cited by 11 publications

(19 citation statements)

References 29 publications

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“…There is evidence that the TRPM4 channel is a critical modulator of ventricular remodelling in cardiac hypertrophy and heart failure (38)(39)(40)42). Previous studies suggest that TRPM4 activation supresses angiotensin II-induced cardiac hypertrophy, dependent on the activation of the calcineurin-NFAT pathway.…”

Section: Discussionmentioning

confidence: 99%

“…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. Consequently, if TRPM4 plays a role in TAC-induced LVH, it acts as an amplifier of the primary Ca 2+ or voltage signal from a yet to be determined mechanosensitive ion channel, or channels.…”

Section: Introductionmentioning

confidence: 99%

“…TRPM4 has been functionally characterized in atrial and ventricular cardiomyocytes, both human and rodent (34)(35)(36). Other studies indicate that TRPM4 contributes to both cardiac function and disease development, including cardiac hypertrophy and heart failure (37)(38)(39)(40)(41). A previous study using Trpm4 cardiomyocyte-specific knock-out (Trpm4 cKO ) mice has shown that TRPM4 is a negative regulator of angiotensin II-induced cardiac hypertrophy in mice, which involves the calcineurin-NFAT pathway (42).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…In many previous studies, only the mRNA expression was described [12,39]. It was similarly present in human and murine hearts [36], and was also detected in rat heart [22,40]. TRPM4 protein is During I Na,L recording, the Tyrode solution contained 1 µM nisoldipine, 100 nM dofetilide, and 100 µM chromanol-293B to eliminate any interference from Ca 2+ and K + currents.…”

Section: Trpm4 Expression In the Canine Heartmentioning

confidence: 99%

Electrophysiological Effects of the Transient Receptor Potential Melastatin 4 Channel Inhibitor (4-Chloro-2-(2-chlorophenoxy)acetamido) Benzoic Acid (CBA) in Canine Left Ventricular Cardiomyocytes

Dienes

Hézsô

Kiss

et al. 2021

IJMS

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Transient receptor potential melastatin 4 (TRPM4) plays an important role in many tissues, including pacemaker and conductive tissues of the heart, but much less is known about its electrophysiological role in ventricular myocytes. Our earlier results showed the lack of selectivity of 9-phenanthrol, so CBA ((4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) was chosen as a new, potentially selective inhibitor. Goal: Our aim was to elucidate the effect and selectivity of CBA in canine left ventricular cardiomyocytes and to study the expression of TRPM4 in the canine heart. Experiments were carried out in enzymatically isolated canine left ventricular cardiomyocytes. Ionic currents were recorded with an action potential (AP) voltage-clamp technique in whole-cell configuration at 37 °C. An amount of 10 mM BAPTA was used in the pipette solution to exclude the potential activation of TRPM4 channels. AP was recorded with conventional sharp microelectrodes. CBA was used in 10 µM concentrations. Expression of TRPM4 protein in the heart was studied by Western blot. TRPM4 protein was expressed in the wall of all four chambers of the canine heart as well as in samples prepared from isolated left ventricular cells. CBA induced an approximately 9% reduction in AP duration measured at 75 and 90% of repolarization and decreased the short-term variability of APD90. Moreover, AP amplitude was increased and the maximal rates of phase 0 and 1 were reduced by the drug. In AP clamp measurements, CBA-sensitive current contained a short, early outward and mainly a long, inward current. Transient outward potassium current (Ito) and late sodium current (INa,L) were reduced by approximately 20 and 47%, respectively, in the presence of CBA, while L-type calcium and inward rectifier potassium currents were not affected. These effects of CBA were largely reversible upon washout. Based on our results, the CBA induced reduction of phase-1 slope and the slight increase of AP amplitude could have been due to the inhibition of Ito. The tendency for AP shortening can be explained by the inhibition of inward currents seen in AP-clamp recordings during the plateau phase. This inward current reduced by CBA is possibly INa,L, therefore, CBA is not entirely selective for TRPM4 channels. As a consequence, similarly to 9-phenanthrol, it cannot be used to test the contribution of TRPM4 channels to cardiac electrophysiology in ventricular cells, or at least caution must be applied.

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“…Moreover, the mechanistic link between TRPCs and Ca 2+ mishandling has been reported in multiple experimental models of cardiac disease including myocardial infarction [ 66 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ], atrial fibrillation [ 88 , 89 , 90 , 91 ], and iron overload cardiomyopathy [ 92 ]. In addition to TRPCs, other members of the TRP superfamily [ 93 , 94 , 95 ], e.g., melastatin (TRPM) [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 ] and vanilloid (TRPV) subtypes [ 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 ], are also potential candidates mediating the non-canonical Ca 2+ entry into cardiomyocytes.…”

Section: Calcium Cycling In Pressure Overload Hypertrophy Dysthyroidism and Human Heart Failurementioning

confidence: 99%

Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

Siri‐Angkul

Dadfar

Jaleel

et al. 2021

IJMS

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The occurrence and prevalence of heart failure remain high in the United States as well as globally. One person dies every 30 seconds from heart disease. Recognizing the importance of heart failure, clinicians and scientists have sought better therapeutic strategies and even cures for end-stage heart failure. This exploration has resulted in many failed clinical trials testing novel classes of pharmaceutical drugs and even gene therapy. As a result, along the way, there have been paradigm shifts toward and away from differing therapeutic approaches. The continued prevalence of death from heart failure, however, clearly demonstrates that the heart is not simply a pump and instead forces us to consider the complexity of simplicity in the pathophysiology of heart failure and reinforces the need to discover new therapeutic approaches.

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TRPM4 Modulates Right Ventricular Remodeling Under Pressure Load Accompanied With Decreased Expression Level

Cited by 11 publications

References 29 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

Electrophysiological Effects of the Transient Receptor Potential Melastatin 4 Channel Inhibitor (4-Chloro-2-(2-chlorophenoxy)acetamido) Benzoic Acid (CBA) in Canine Left Ventricular Cardiomyocytes

Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

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TRPM4 Modulates Right Ventricular Remodeling Under Pressure Load Accompanied With Decreased Expression Level

Cited by 11 publications

References 29 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

Electrophysiological Effects of the Transient Receptor Potential Melastatin 4 Channel Inhibitor (4-Chloro-2-(2-chlorophenoxy)acetamido) Benzoic Acid (CBA) in Canine Left Ventricular Cardiomyocytes

Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

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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