Transient receptor potential vanilloid-4 contributes to stretch-induced hypercontractility and time-dependent dysfunction in the aged heart

Abstract Aims Cardiovascular disease remains the greatest cause of mortality in Americans over 65. The stretch-activated transient receptor potential vanilloid-4 (TRPV4) ion channel is expressed in cardiomyocytes of the aged heart. This investigation tests the hypothesis that TRPV4 alters Ca2+ handling and cardiac function in response to increased ventricular preload and cardiomyocyte stretch. Methods and results Left ventricular maximal pressure (PMax) was monitored in isolated working hearts of Aged (24–27 months) mice following preload elevation from 5 to 20mmHg, with and without TRPV4 antagonist HC067047 (HC, 1 µmol/L). In preload responsive hearts, PMax prior to and immediately following preload elevation (i.e. Frank–Starling response) was similar between Aged and Aged+HC. Within 1 min following preload elevation, Aged hearts demonstrated secondary PMax augmentation (Aged>Aged+HC) suggesting a role for stretch-activated TRPV4 in cardiac hypercontractility. However, after 20 min at 20 mmHg Aged exhibited depressed PMax (Aged<Aged+HC) suggestive of TRPV4-dependent contractile dysfunction with sustained stretch. To examine stretch-induced Ca2+ homeostasis at the single-cell level, isolated cardiomyocytes were stretched 10–15% of slack length while measuring intracellular Ca2+ with fura-2. Uniaxial longitudinal stretch increased intracellular Ca2+ levels and triggered Ca2+ overload and terminal cellular contracture in Aged, but not Aged+HC. Preload elevation in hearts of young/middle-age (3–12 months) mice produced an initial PMax increase (Frank–Starling response) without secondary PMax augmentation, and cardiomyocyte stretch did not affect intracellular Ca2+ levels. Hearts of transgenic mice with cardiac-specific TRPV4 expression exhibited PMax similar to 3- to 12-month control mice prior to and immediately following preload elevation but displayed secondary PMax augmentation. Cardiomyocytes of mice with transgenic TRPV4 expression were highly sensitive to mechanical stimulation and exhibited elevated Ca2+ levels, Ca2+ overload, and terminal contracture upon cellular attachment and stretch. Conclusion TRPV4 contributes to a stretch-induced increase in cardiomyocyte Ca2+ and cardiac hypercontractility, yet sustained stretch leads to cardiomyocyte Ca2+ overload and contractile dysfunction in the aged heart.

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Transient Receptor Potential Vanilloid 4 channel participates in mouse ventricular electrical activity

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00497.2020 ◽

2021 ◽

Author(s):

Sebastien Chaigne ◽

Guillaume Cardouat ◽

Julien Louradour ◽

Fanny Vaillant ◽

Sabine Charron ◽

...

Keyword(s):

Action Potential ◽

Electrical Activity ◽

Transient Receptor Potential ◽

Ventricular Myocytes ◽

Receptor Potential ◽

Left Ventricular ◽

Transient Receptor Potential Vanilloid ◽

Western Blots ◽

Transient Receptor ◽

Trpv4 Channel

Introduction: Transient Receptor Potential Vanilloid 4 (TRPV4) channel is a calcium permeable channel (PCa/PNa ~ 10). Its expression was reported in ventricular myocytes where it is involved in several cardiac pathological mechanisms. In this study, we investigated the implication of TRPV4 in ventricular electrical activity. Methods and Results: Left ventricular myocytes were isolated from trpv4+/+ and trpv4-/- mice. TRPV4 membrane expression and its colocalization with Cav1.2 was confirmed using western-blots biotinylation, immunoprecipitation and immunostaining experiments. Then, electrocardiograms (ECGs) and patch-clamp recordings showed shortened QTc and action potential (AP) duration in trpv4-/- compared to trpv4+/+ mice. Thus, TRPV4 activator GSK1016790A produced a transient and dose-dependent increase in AP duration at 90 % of repolarization (APD90) in trpv4+/+, but not in trpv4-/- myocytes or when combined with TRPV4 inhibitor GSK2193874 (100 nM). Hence, GSK1016790A increased CaT amplitude in trpv4+/+ but not in trpv4-/- myocytes, suggesting that TRPV4 carries an inward Ca2+ current in myocytes. Conversely, TRPV4 inhibitor GSK2193874 (100 nM) alone reduced APD90 in trpv4+/+ but not in trpv4-/- myocytes, suggesting that TRPV4 prolongs AP duration (APD) in basal condition. Finally, introducing TRPV4 parameters in a mathematical model predicted the development of an inward TRPV4 current during repolarization that increases AP duration and CaT amplitude, in accordance with what found experimentally. Conclusion: This study shows for the first time that TRPV4 modulates AP and QTc durations and constitutes thereby a good therapeutical target against long QT-mediated ventricular arrhythmias. Keywords: TRPV4 channel, action potential, QT interval, mathematical modeling, trpv4-/-, calcium transient.

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Protease-activated receptor 2-mediated protection of myocardial ischemia-reperfusion injury: role of transient receptor potential vanilloid receptors

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90746.2008 ◽

2009 ◽

Vol 297 (6) ◽

pp. R1681-R1690 ◽

Cited By ~ 31

Author(s):

Beihua Zhong ◽

Donna H. Wang

Keyword(s):

Transient Receptor Potential ◽

Diastolic Pressure ◽

Ischemia Reperfusion ◽

Left Ventricular Pressure ◽

Receptor Potential ◽

Left Ventricular ◽

Transient Receptor Potential Vanilloid ◽

Transient Receptor ◽

Myocardial Ischemia Reperfusion ◽

Developed Pressure

Activation of the protease-activated receptor 2 (PAR2) or the transient receptor potential vanilloid type 1 (TRPV1) channels expressed in cardiac sensory afferents containing calcitonin gene-related peptide (CGRP) and/or substance P (SP) has been proposed to play a protective role in myocardial ischemia-reperfusion (I/R) injury. However, the interaction between PAR2 and TRPV1 is largely unknown. Using gene-targeted TRPV1-null mutant (TRPV1−/−) or wild-type (WT) mice, we test the hypothesis that TRPV1 contributes to PAR2-mediated cardiac protection via increasing the release of CGRP and SP. Immunofluorescence labeling showed that TRPV1 coexpressed with PAR2, PKC-ε, or PKAc in cardiomyocytes, cardiac blood vessels, and perivascular nerves in WT but not TRPV1−/− hearts. WT or TRPV1−/− hearts were Langendorff perfused with the selective PAR2 agonist, SLIGRL, in the presence or absence of various antagonists, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). The recovery rate of coronary flow, the maximum rate of left ventricular pressure development, left ventricular end-diastolic pressure, and left ventricular developed pressure were evaluated after I/R. SLIGRL improved the recovery of hemodynamic parameters, decreased lactate dehydrogenase release, and reduced the infarct size in both WT and TRPV1−/− hearts ( P < 0.05). The protection of SLIGRL was significantly surpassed for WT compared with TRPV1−/− hearts ( P < 0.05). CGRP8–37, a selective CGRP receptor antagonist, RP67580, a selective neurokinin-1 receptor antagonist, PKC-ε V1–2, a selective PKC-ε inhibitor, or H-89, a selective PKA inhibitor, abolished SLIGRL protection by inhibiting the recovery of the rate of coronary flow, maximum rate of left ventricular pressure development, and left ventricular developed pressure, and increasing left ventricular end-diastolic pressure in WT but not TRPV1−/− hearts. Radioimmunoassay showed that SLIGRL increased the release of CGRP and SP in WT but not TRPV1−/− hearts ( P < 0.05), which were prevented by PKC-ε V1–2 and H-89. Thus our data show that PAR2 activation improves cardiac recovery after I/R injury in WT and TRPV1−/− hearts, with a greater effect in the former, suggesting that PAR2-mediated protection is TRPV1 dependent and independent, and that dysfunctional TRPV1 impairs PAR2 action. PAR2 activation of the PKC-ε or PKA pathway stimulates or sensitizes TRPV1 in WT hearts, leading to the release of CGRP and SP that contribute, at least in part, to PAR2-induced cardiac protection against I/R injury.

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