The Ca2+-activated cation channel TRPM4 is a negative regulator of angiotensin II-induced cardiac hypertrophy

Abstract

Cardiac muscle adapts to hemodynamic stress by altering myocyte size and function, resulting in cardiac hypertrophy. Alteration in myocyte calcium homeostasis is known to be an initial signal in cardiac hypertrophy signaling. Transient receptor potential melastatin 4 protein (TRPM4) is a calcium-activated non-selective cation channel, which plays a role in regulating calcium influx and calcium-dependent cell functions in many cell types including cardiomyocytes. Selective deletion of TRPM4 from the heart muscle in mice resulted in an increased hypertrophic growth after chronic angiotensin (AngII) treatment, compared to WT mice. The enhanced hypertrophic response was also traceable by the increased expression of hypertrophy-related genes like Rcan1, ANP, and α-Actin. Intracellular calcium measurements on isolated ventricular myocytes showed significantly increased store-operated calcium entry upon AngII treatment in myocytes lacking the TRPM4 channel. Elevated intracellular calcium is a key factor in the development of pathological cardiac hypertrophy, leading to the activation of intracellular signaling pathways. In agreement with this, we observed significantly higher Rcan1 mRNA level, calcineurin enzyme activity and protein level in lysates from TRPM4-deficient mice heart compared to WT after AngII treatment. Collectively, these observations are consistent with a model in which TRPM4 is a regulator of calcium homeostasis in cardiomyocytes after AngII stimulation. TRPM4 contributes to the regulation of driving force for store-operated calcium entry and thereby the activation of the calcineurin–NFAT pathway and the development of pathological hypertrophy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-015-0501-x) contains supplementary material, which is available to authorized users.

Differential expression of store-operated calcium- and proliferation-related genes in hepatocellular carcinoma cells following TRPC1 ion channel silencing

“…TRPC6 up-regulation was unable to be replicated in the present study due to the limitations of the microarray technology, where TRPC6 was not detectably expressed in our samples. In addition to TRPC1, TRPM4 was recently shown to be a negative regulator of SOC entry [21]. Although TRPM4 levels were positively correlated with down-regulation of TRPC1 , TRPM4 expression was not significantly changed in our study possibly indicating that they function independently but also potentially due to tissue-specific variations in SOC entry regulatory mechanisms.…”

TRPM4 expression is associated with activated B cell subtype and poor survival in diffuse large B cell lymphoma

“…Excessive activation of TRPM4 is associated with various non‐malignant disorders and has been proposed to be a putative target for inhibition in numerous cardiovascular disorders and hypertension, oxidative stress‐mediated inflammatory diseases and multiple sclerosis . Trpm4 −/− mice were shown to be viable and fertile without obvious anatomical abnormalities, TRPM4‐selective inhibitor 9‐phenanthrol exerted cardioprotective effects, while the Human Protein Atlas consortium included TRPM4 as one of the 1054 potentially druggable proteins of the human proteome, indicating that TRPM4 represents a potential experimental target.…”

“…Excessive activation of TRPM4 is associated with various non-malignant disorders and has been proposed to be a putative target for inhibition in numerous cardiovascular disorders and hypertension, [45][46][47][48][49] oxidative stress-mediated inflammatory diseases 10 and multiple sclerosis. 50 Trpm4 À/À mice were shown to be viable and fertile without obvious anatomical abnormalities, 51 TRPM4-selective inhibitor 9-phenanthrol We demonstrated that TRPM4-positive DLBCL patients treated with R-CHOP exhibited significantly worse survival, consistent with its expression being associated with adverse clinical parameters.…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…Recently, a background Ca 2ϩ entry pathway in cardiac myocytes formed by TRPC1 and TRPC4 channels was implicated in ANG II-induced hypertrophy as well (113). In contrast, the Ca 2ϩ -activated cation channel TRPM4 was identified as a negative regulator of ANG II-induced cardiac hypertrophy, ostensibly by inducing a depolarizing current that attenuates Ca 2ϩ sarcolemmal entry, thus limiting filling of the IP 3 -sensitive Ca 2ϩ stores (475). D) ␤-ARRESTIN.…”