Contribution of TRPV4 to enhanced calcium cycling and cardiac arrhythmia following ischemia-reperfusion in aged mouse hearts

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI--COLUMBIA AT REQUEST OF AUTHOR.] Cardiomyocyte Ca2+ homeostasis is altered with aging and predisposes the Aged heart to Ca2+ intolerance and arrhythmia. Transient Receptor Potential Vanilloid 4 (TRPV4) is an osmotically-activated cation channel and channel expression is increased in cardiomyocytes of Aged mice. The central goal of this work was to determine the role of TRPV4 in calcium handling and arrhythmogenesis in response to hypoosmotic stress and following ischemia-reperfusion (I/R). Hypoosmotic stress induced an increase in calcium transient amplitude in cardiomyocytes isolated from Aged mice which was followed by an increased incidence of arrhythmic Ca2+ events and Ca2+ waves. This effect was prevented by TRPV4 inhibition and was absent in cardiomyocytes from Young mice. Cardiac contractile function, membrane potential, and cardiac ECG was monitored in Langendorff-perfused hearts during I/R. Aged hearts responded to I/R with an initial increase in contractile function, membrane depolarization, and incidence of ventricular arrhythmia during reperfusion. This effect was attenuated by TRPV4 inhibition and was absent in hearts of Young mice. Also, in hearts of Aged, TRPV4 inhibition decreased the percent of damaged tissue following I/R compared to untreated conditions. Finally, Langendorff-perfused hearts from Aged mice expressing a genetically encoded Ca2+ sensor (GCaMP6f) were subjected to I/R and demonstrated an increased Ca2+ transient amplitude and incidence of arrhythmic Ca2+ waves compared to Aged mice treated with TRPV4 inhibition. These findings suggest that TRPV4 may contribute to initial inotropy followed by pro-arrhythmic cardiomyocyte Ca2+ signaling, arrhythmogenesis, and cell death following I/R in the Aged heart.