Tranilast Blunts the Hypertrophic and Fibrotic Response to Increased Afterload Independent of Cardiomyocyte Transient Receptor Potential Vanilloid 2 Channels

Koch, Sheryl E.; Nieman, Michelle L.; Robbins, Nathan; Slone, Samuel; Worley, Mariah; Green, Lisa C; Yamei, Chen; Barlow, Alexandria; Tranter, Michael; Wang, HongSheng; Lorenz, John N.; Rubinstein, Jack

doi:10.1097/fjc.0000000000000588

Cited by 10 publications

(9 citation statements)

References 28 publications

(51 reference statements)

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“…A knockout of TRPV2 in mice also reduces age-related fibrosis and hypertrophy [210]. Application of the TRPV2 blocker Tranilast blunts the hypertrophic and fibrotic response to pressure-overload-induced hypertrophy within four weeks [180]. Although TRPV2 has been shown to be located intracellularly and translocates to the sarcolemma under stress, the effect of Tranilast does not seem to be mediated through its effects on myocytes [180].…”

Section: Trpv2 and Cardiac Fibrosismentioning

confidence: 99%

“…Application of the TRPV2 blocker Tranilast blunts the hypertrophic and fibrotic response to pressure-overload-induced hypertrophy within four weeks [180]. Although TRPV2 has been shown to be located intracellularly and translocates to the sarcolemma under stress, the effect of Tranilast does not seem to be mediated through its effects on myocytes [180]. TRPV2 is also expressed in other cell types, such as macrophages, and in fact, TRPV2 knockout improves heart performance after myocardial infarction due to attenuated activity of peri-infarct macrophages [181].…”

Section: Trpv2 and Cardiac Fibrosismentioning

confidence: 99%

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Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Feng

Armillei

et al. 2019

JCDD

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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.

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Section: Trpv2 and Cardiac Fibrosismentioning

confidence: 99%

Section: Trpv2 and Cardiac Fibrosismentioning

confidence: 99%

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Feng

Armillei

et al. 2019

JCDD

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“…Furthermore, the non-selective TRPV2 blocker tranilast blunted the hypertrophic and fibrotic responses induced by transverse aortic constriction in vivo after 4 weeks and was associated with improved cardiac function, but after longer administration (8 weeks) cardiac function was similar to the control group. In vitro studies showed tranilast response was not at the cardiomyocyte level [ 27 ]. The stimulation of TRPV2 with the TRPV2 agonist probenecid (100 mg/kg intravenously) had a positive inotropic effect, which was absent in TRPV2 -/- mice.…”

Section: The Role Of Trpv In the Regulation Of The Cardiac Contractility And Vascular Relaxationmentioning

confidence: 99%

Physiological and Pathological Role of TRPV1, TRPV2 and TRPV4 Channels in Heart

Gorbunov

Маслов

Jaggi

et al. 2019

CCR

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Transient receptor potential vanilloid channel 2 (TRPV2) is required for normal cardiac contractility. The stimulation of TRPV1 in isolated cardiomyocytes can aggravate the effect of hypoxia/ reoxygenation (H/R) on H9C2 cells. The knockout of the TRPV1 gene promotes increased tolerance of the isolated perfused heart to the impact of ischemia/reperfusion (I/R). However, activation of TRPV1 increases the resistance of the heart to I/R due to calcitonin gene-related peptide (CGRP) release from afferent nerve endings. It has been established that TRPV1 and TRPV2 are involved in the pathogenesis of myocardial infarction and, in all likelihood, ensure the cardiac tolerance to the ischemia/reperfusion. It has also been documented that the activation of TRPV4 negatively affects the stability of cardiomyocytes to the H/R. The blockade of TRPV4 can be considered as a new approach to the prevention of I/R injury of the heart. Studies also indicate that TRPV1 is involved in the pathogenesis of cardiac hypertrophy and that TRPV2 channels participate in the pathogenesis of dilated cardiomyopathy. Excessive expression of TRPV2 leads to chronic Ca2+- overload of cardiomyocytes, which may contribute to the development of cardiomyopathy.

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“…The most effective known inhibitors are ruthenium red (RR) and trivalent cations, but these function as non-specific channel blockers 2,23,24 . Tranilast, an antiallergic drug, has been suggested to inhibit TRPV2 2 , but this was called into question when a recent study showed that tranilast has no direct effect on TRPV2 in vivo 25 .…”

Section: Introductionmentioning

confidence: 99%

TRPV2 interaction with small molecules and lipids revealed by cryo-EM

Protopopova

Pumroy

Haug

et al. 2020

Preprint

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Transient receptor potential vanilloid 2 (TRPV2) plays a critical role in a variety of physiological and pathophysiological processes, putting TRPV2 on the list of important drug targets. Yet, specific TRPV2 agonists and antagonists are currently unavailable. Their development requires a precise knowledge of how the currently known non-specific small molecules interact with TRPV2 at the molecular level. Here we present TRPV2 structures in ligand-bound states resolved by cryo-electron microscopy in the presence of 2-aminoethoxydiphenyl borate (2-ABP), 2-APB with doxorubicin (DOXO), and ruthenium red (RR). We identified a novel 2-APB drug binding site between the S5 helix and S4-S5 linker on two adjacent TRPV2 monomers and determined the mechanism of TRPV2 pore block by RR. We also showed that a large organic molecule like DOXO can enter the TRPV2 pore in the presence of 2-APB. Additionally, we discovered a structural lipid bound in a unique position in the vanilloid pocket, which is absent in the 2-APB-bound state of the channel, allowing us to propose a model for TRPV2 channel gating. Together, this work provides a further understanding of TRPV2 function and a structural framework for the development of TRPV2-specific modulators.

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Tranilast Blunts the Hypertrophic and Fibrotic Response to Increased Afterload Independent of Cardiomyocyte Transient Receptor Potential Vanilloid 2 Channels

Cited by 10 publications

References 28 publications

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Physiological and Pathological Role of TRPV1, TRPV2 and TRPV4 Channels in Heart

TRPV2 interaction with small molecules and lipids revealed by cryo-EM

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