Transient receptor potential vanilloid 2 function regulates cardiac hypertrophy via stretch-induced activation

Koch, Sheryl E.; Mann, Adrien; Jones, Shannon; Robbins, Nathan; Alkhattabi, Abdullah; Worley, Mariah; Gao, Xu; Lasko-Roiniotis, Valerie M.; Karani, Rajiv; Fulford, Logan; Jiang, Min; Nieman, Michelle L.; Lorenz, John N.; Rubinstein, Jack

doi:10.1097/hjh.0000000000001213

Cited by 24 publications

(30 citation statements)

References 36 publications

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“…The Hsp20-S10F PPCM model also had significantly increased mRNA levels of ANP, consistent with the development of pathological hypertrophy. Additionally, TRPV2 has been found by our laboratory, as well as others, to be a stretch activated channel that increases expression under stress/stretch conditions [47,48]. In this model, we found that TRPV2 expression did not change in WT mice, but was significantly higher in untreated Hsp20-S10F mice in comparison to the treated which is consistent with the observed LV remodeling in the untreated mice.…”

Section: Discussionsupporting

confidence: 90%

“…These findings are still of course preliminary. Further, the generalizability of the TRPV2 findings to human population will require further study since even though our data in animals demonstrated increased TRPV2 expression in response to stress [47], some researchers have reported decreased TRPV2 expression in human subjects with heart failure [50], while others have found no difference [51].…”

Section: Discussionmentioning

confidence: 79%

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Probenecid treatment improves outcomes in a novel mouse model of peripartum cardiomyopathy

et al. 2020

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Probenecid has been used for decades in the treatment of gout but recently has also been found to improve outcomes in patients with heart failure via stimulation of the transient receptor potential vanilloid 2 (TRPV2) channel in cardiomyocytes. This study tested the use of probenecid on a novel mouse model of peripartum cardiomyopathy (PPCM) as a potential treatment option. A human mutation of the human heat shock protein 20 (Hsp20-S10F) in mice has been recently shown to result in cardiomyopathy, when exposed to pregnancies. Treatment with either probenecid or control sucrose water was initiated after the first pregnancy in both wild type and Hsp20-S10F mice. Serial echocardiography was performed during subsequent pregnancies and hearts were collected after the third pregnancies for staining and molecular analysis. Hsp20-S10F mice treated with probenecid had decreased mortality, hypertrophy, TRPV2 expression and molecular parameters of heart failure. Probenecid treatment also decreased apoptosis as evidenced by an increase in the level of Bcl-2/Bax. Probenecid improved survival in a novel mouse model of PPCM and may be an appropriate therapy for humans with PPCM as it has a proven safety and tolerability in patients with heart failure.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 79%

Probenecid treatment improves outcomes in a novel mouse model of peripartum cardiomyopathy

et al. 2020

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“…TRPV2 has been shown to play a role in Ca 2+ -induced myocyte degeneration in dilated cardiomyopathy [178]. A knockout of TRPV2 protects hearts against pressure-overload-induced hypertrophy, but produces no protection against AngII or β-adrenergic activation-induced hypertrophy, indicating that TRPV2 regulates cardiac hypertrophy through stretch activation [179]. A knockout of TRPV2 in mice also reduces age-related fibrosis and hypertrophy [210].…”

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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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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“…14 Iwata et al initially described that cardiac-specific overexpression of TRPV2 resulted in chamber dilation of all cavities of the murine heart, 15 while our laboratory recently demonstrated increased expression of TRPV2 in diseased hearts. 16 Related studies by our laboratory demonstrated that stimulation of the channel with probenecid in isolated cardiomyocytes resulted in increased cytosolic calcium concentrations with improved contractility and relaxation, independently of the b-adrenergic signaling pathway. 17 Further translational studies in healthy and infarcted mice confirmed that probenecid results in improved inotropy and lusitropy in a dose-dependent manner and does not induce malignant arrhythmias or apoptosis.…”

mentioning

confidence: 94%

“…Expression of the transient receptor potential vanilloid 2 (TRPV2) channel was noted in abundance in murine myocardial tissue, specifically in the left ventricle 14. Iwata et al initially described that cardiac‐specific overexpression of TRPV2 resulted in chamber dilation of all cavities of the murine heart,15 while our laboratory recently demonstrated increased expression of TRPV2 in diseased hearts 16. Related studies by our laboratory demonstrated that stimulation of the channel with probenecid in isolated cardiomyocytes resulted in increased cytosolic calcium concentrations with improved contractility and relaxation, independently of the β‐adrenergic signaling pathway 17.…”

Section: Introductionmentioning

confidence: 99%

Probenecid Improves Cardiac Function in Patients With Heart Failure With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium Sensitivity In Vitro

Robbins

Gilbert

Kumar

et al. 2018

JAHA

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BackgroundTransient receptor potential vanilloid 2 is a calcium channel activated by probenecid. Probenecid is a Food and Drug Administration–approved uricosuric drug that has recently been shown to induce positive lusitropic and inotropic effects in animal models through cardiomyocyte transient receptor potential vanilloid 2 activation. The aim of this study was to test the hypothesis that oral probenecid can improve cardiac function and symptomatology in patients with heart failure with reduced ejection fraction and to further elucidate its calcium‐dependent effects on myocyte contractility.Methods and ResultsThe clinical trial recruited stable outpatients with heart failure with reduced ejection fraction randomized in a single‐center, double‐blind, crossover design. Clinical data were collected including a dyspnea assessment, physical examination, ECG, echocardiogram to assess systolic and diastolic function, a 6‐minute walk test, and laboratory studies. In vitro force generation studies were performed on cardiomyocytes isolated from murine tissue exposed to probenecid or control treatments. The clinical trial recruited 20 subjects (mean age 57 years, mean baseline fractional shortening of 13.6±1.0%). Probenecid therapy increased fractional shortening by 2.1±1.0% compared with placebo −1.7±1.0% (P=0.007). Additionally, probenecid improved diastolic function compared with placebo by decreasing the E/E′ by −2.95±1.21 versus 1.32±1.21 in comparison to placebo (P=0.03). In vitro probenecid increased myofilament force generation (92.36 versus 80.82 mN/mm2, P<0.05) and calcium sensitivity (pCa 5.67 versus 5.60, P<0.01) compared with control.ConclusionsProbenecid improves cardiac function with minimal effects on symptomatology and no significant adverse effects after 1 week in patients with heart failure with reduced ejection fraction and increases force development and calcium sensitivity at the cardiomyocyte level.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01814319.

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Transient receptor potential vanilloid 2 function regulates cardiac hypertrophy via stretch-induced activation

Abstract: We conclude that TRPV2 function, as a stretch-activated channel, regulates the development of cardiomyocyte hypertrophy in response to increased afterload.

Cited by 24 publications

References 36 publications

Probenecid treatment improves outcomes in a novel mouse model of peripartum cardiomyopathy

Probenecid treatment improves outcomes in a novel mouse model of peripartum cardiomyopathy

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

Probenecid Improves Cardiac Function in Patients With Heart Failure With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium Sensitivity In Vitro

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