Stretch-activated TRPV2 channels: Role in mediating cardiopathies

Aguettaz, E.; Bois, Patrick; Cognard, Christian; Sebille, Stéphane

doi:10.1016/j.pbiomolbio.2017.05.007

Cited by 25 publications

(24 citation statements)

References 58 publications

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“…These inflammatory cytokines can alter cardiac electrophysiology by modulating functional protein expression in myocytes ( Hansen et al, 1994 ; Fernandez-Cobo et al, 1999 ; Fernández-Velasco et al, 2007 ; Chappell et al, 2009 ; Grandy and Fiset, 2009 ; Guillouet et al, 2011 ). Furthermore, we have demonstrated that perinexal width can be modulated by extracellular free calcium concentrations and osmotic stress, both of which could also alter cardiac electrophysiology via second messenger pathways and stretch-activated channels ( Aguettaz et al, 2017 ). While the relative changes to perinexal width are small, they are similar to what has been previously reported experimentally and what has been suggested mathematically as being electrophysiologically relevant ( Mori et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Intercalated Disk Extracellular Nanodomain Expansion in Patients With Atrial Fibrillation

et al. 2018

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Aims: Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous evidence in animal models suggests that the gap junction (GJ) adjacent nanodomain – perinexus – is a site capable of independent intercellular communication via ephaptic transmission. Perinexal expansion is associated with slowed conduction and increased ventricular arrhythmias in animal models, but has not been studied in human tissue. The purpose of this study was to characterize the perinexus in humans and determine if perinexal expansion associates with AF.Methods: Atrial appendages from 39 patients (pts) undergoing cardiac surgery were fixed for immunofluorescence and transmission electron microscopy (TEM). Intercalated disk distribution of the cardiac sodium channel Nav1.5, its β1 subunit, and connexin43 (C×43) was determined by confocal immunofluorescence. Perinexal width (Wp) from TEM was manually segmented by two blinded observers using ImageJ software.Results: Nav1.5, β1, and C×43 are co-adjacent within intercalated disks of human atria, consistent with perinexal protein distributions in ventricular tissue of other species. TEM revealed that the GJ adjacent intermembrane separation in an individual perinexus does not change at distances greater than 30 nm from the GJ edge. Importantly, Wp is significantly wider in patients with a history of AF than in patients with no history of AF by approximately 3 nm, and Wp correlates with age (R = 0.7, p < 0.05).Conclusion: Human atrial myocytes have voltage-gated sodium channels in a dynamic intercellular cleft adjacent to GJs that is consistent with previous descriptions of the perinexus. Further, perinexal width is greater in patients with AF undergoing cardiac surgery than in those without.

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Section: Discussionmentioning

confidence: 99%

Intercalated Disk Extracellular Nanodomain Expansion in Patients With Atrial Fibrillation

et al. 2018

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“…TRP vanilloid type 2 (TRPV2) is a Ca 2+ permeable stretch-activated channel [94]. TRPV4 is also stimulated by mechanical stress, including sheer stress and cell swelling, and has been implicated in regulation of myogenic tone [52].…”

Section: Ca2+ Influx From the Extracellular Spacementioning

confidence: 99%

Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease

Liu

Khalil

2018

Biochemical Pharmacology

125

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Vascular smooth muscle (VSM) plays an important role in the regulation of vascular function. Identifying the mechanisms of VSM contraction has been a major research goal in order to determine the causes of vascular dysfunction and exaggerated vasoconstriction in vascular disease. Major discoveries over several decades have helped to better understand the mechanisms of VSM contraction. Ca has been established as a major regulator of VSM contraction, and its sources, cytosolic levels, homeostatic mechanisms and subcellular distribution have been defined. Biochemical studies have also suggested that stimulation of Gq protein-coupled membrane receptors activates phospholipase C and promotes the hydrolysis of membrane phospholipids into inositol 1,4,5-trisphosphate (IP) and diacylglycerol (DAG). IP stimulates initial Ca release from the sarcoplasmic reticulum, and is buttressed by Ca influx through voltage-dependent, receptor-operated, transient receptor potential and store-operated channels. In order to prevent large increases in cytosolic Ca concentration ([Ca]), Ca removal mechanisms promote Ca extrusion via the plasmalemmal Ca pump and Na/Ca exchanger, and Ca uptake by the sarcoplasmic reticulum and mitochondria, and the coordinated activities of these Ca handling mechanisms help to create subplasmalemmal Ca domains. Threshold increases in [Ca] form a Ca-calmodulin complex, which activates myosin light chain (MLC) kinase, and causes MLC phosphorylation, actin-myosin interaction, and VSM contraction. Dissociations in the relationships between [Ca], MLC phosphorylation, and force have suggested additional Ca sensitization mechanisms. DAG activates protein kinase C (PKC) isoforms, which directly or indirectly via mitogen-activated protein kinase phosphorylate the actin-binding proteins calponin and caldesmon and thereby enhance the myofilaments force sensitivity to Ca. PKC-mediated phosphorylation of PKC-potentiated phosphatase inhibitor protein-17 (CPI-17), and RhoA-mediated activation of Rho-kinase (ROCK) inhibit MLC phosphatase and in turn increase MLC phosphorylation and VSM contraction. Abnormalities in the Ca handling mechanisms and PKC and ROCK activity have been associated with vascular dysfunction in multiple vascular disorders. Modulators of [Ca], PKC and ROCK activity could be useful in mitigating the increased vasoconstriction associated with vascular disease.

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“…Recent studies using rodent models of transverse aortic constriction (TAC)-induced heart failure [12], myocardial infarction (MI) [13,14], and chemotherapy-induced cardiomyopathy [9] showed that the enhanced TRPV2 expression was associated with cardiac dysfunction and that TRPV2 plays an important role in general heart failure and cardiomyopathy [15].…”

Section: Muscular Dysgenesis and Trpv2mentioning

confidence: 99%

Blockade of TRPV2 is a Novel Therapy for Cardiomyopathy in Muscular Dystrophy

Iwata

Matsumura

2019

IJMS

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Muscular dystrophy and dilated cardiomyopathy are intractable diseases and their treatment options are very limited. Transient receptor potential cation channel subfamily V, member 2 (TRPV2), is a stretch-sensitive Ca2+-permeable channel that causes sustained intracellular Ca2+ increase in muscular cells, which is a pathophysiological feature of degenerative muscular disease. Recent reports have clarified that TRPV2 is concentrated and activated in the sarcolemma of cardiomyocytes/myocytes during cardiomyopathy/heart failure and muscular dystrophy. Furthermore, these reports showed that inactivation of TRPV2 ameliorates muscle dysgenesis to improve cardiac function and survival prognosis. Although TRPV2 is a potential therapeutic target for cardiomyopathy, there were no TRPV2 inhibitors available until recently. In this review, we introduce our recent findings and discuss the current progress in the development of TRPV2 inhibitors and their therapeutic applications for cardiomyopathy associated with muscular dystrophy.

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Stretch-activated TRPV2 channels: Role in mediating cardiopathies

Cited by 25 publications

References 58 publications

Intercalated Disk Extracellular Nanodomain Expansion in Patients With Atrial Fibrillation

Intercalated Disk Extracellular Nanodomain Expansion in Patients With Atrial Fibrillation

Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease

Blockade of TRPV2 is a Novel Therapy for Cardiomyopathy in Muscular Dystrophy

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