Abstract
The Transient Receptor Potential (TRP) ion channel family plays an important role in cardiomyocyte calcium homeostasis, particularly in diseased states. Here, we test the hypothesis that the osmotically-activated TRP Vanilloid 4 (TRPV4) channel enhances cardiomyocyte calcium transients in the aged heart following hypoosmotic stress. Expression of TRPV4 was low in cardiomyocytes of Young (3-6 month) mice, but significantly increased in cardiomyocytes of Aged (24-26 month) mice. In cardiomyocytes of Aged, hypoosmotic stress (250 mOsm) induced an increase in calcium transient amplitude (F/F0:3.6±0.1 hypoosmotic versus 2.9±0.2 isosmotic, P<0.05). This effect was prevented by the TRPV4 inhibitor HC067047 (1 μM, F/F0:2.9±0.1 hypoosmotic) and was absent in cardiomyocytes of Young mice (F/F0:3.2±0.1 hypoosmotic versus 2.9±0.2 isosmotic). However, cardiomyocytes of Young mice with cardiac-specific TRPV4 Overexpression exhibited enhanced calcium transient amplitude following hypoosmotic stress (F/F0:3.5±0.2 hypoosmotic versus 2.4±0.1 isosmotic, P<0.05) that was prevented by HC067047 (F/F0:2.6±0.1 hypoosmotic). Ischemia-reperfusion (I-R) injury is a pathological scenario associated with pronounced osmotic stress on cardiomyocytes. We therefore monitored left-ventricular pressure development in Langendorff-perfused hearts of Young, Aged, Young TRPV4 Overexpressor, and Aged TRPV4 knock-out mice subjected to 45 minute global ischemia followed by reperfusion. Prior to ischemia, all hearts exhibited similar contractility (dP/dtMax range: 1934±206 to 2226±62 mmHg/s). Following I-R, hearts of Aged mice exhibited enhanced contractile performance (dP/dtMax: 2770±180 mmHg/s) versus hearts of Aged TRPV4 knock-out mice (dP/dtMax: 1400±300 mmHg/s, P<0.05). Similarly, hearts of Young TRPV4 Overexpressor mice exhibited enhanced contractile performance (dP/dtMax: 2750±180 mmHg/s) versus hearts of Young mice (dP/dtMax: 1650±260 mmHg/s, P<0.05). In conclusion, TRPV4 enhances calcium transients following hypoosmotic stress and contributes to hypercontractility following I-R. Our findings have potential clinical implications in the treatment of elderly populations at increased risk of myocardial infarction and reperfusion injury.
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