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Article Abstract
Background: Transient receptor potential vanilloid 4 (TRPV4), a calcium (Ca) permeable channel, is upregulated during myocardial ischemia-reperfusion (IR). Although TRPV4 inhibition has cardioprotective effects, its impact on arrhythmogenesis remains unclear.
Objective: This study aimed to evaluate the antiarrhythmic effects of TRPV4 inhibition, using the TRPV4 antagonist GSK2193874 (GSK219) and TRPV4 knockout (TRPV4) mice, after IR.
Methods: Surface electrocardiogram and optical mapping recordings were performed during 15 minutes of global ischemia and 10 minutes of reperfusion in Langendorff perfused mouse hearts. Ca sparks were detected by confocal microscopy, and protein expression was analyzed by Western blot.
Results: GSK219 or TRPV4 deletion significantly decreased the incidence and duration of ventricular tachycardia during reperfusion. TRPV4 inhibition shortened Ca transient (CaT) recovery, suppressed CaT alternans, and decreased Ca leak without affecting IR-induced prolongation of action potential duration (APD) and APD alternations. Activation of TRPV4 by GSK101790A (GSK101) increased arrhythmia susceptibility and Ca leak. Moreover, GSK101 prolonged CaT recovery and promoted CaT alternans, which were greatly avoided by pretreatment with Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor. Interestingly, IR or GSK101 markedly increased the phosphorylation of CaMKII, ryanodine receptors, and phospholamban, which was significantly blocked by TRPV4 inhibition.
Conclusion: TRPV4 inhibition exerts antiarrhythmic effects after IR by modulating CaMKII-dependent Ca handling abnormalities, reducing CaT alternans and Ca leak, without affecting APD.
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| http://dx.doi.org/10.1016/j.hrthm.2025.04.006 | DOI Listing |
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