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

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.

Left ventricular maximal pressure (P_Max) 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, P_Max 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 P_Max augmentation (Aged>Aged+HC) suggesting a role for stretch-activated TRPV4 in cardiac hypercontractility. However, after 20 min at 20 mmHg Aged exhibited depressed P_Max (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 P_Max increase (Frank–Starling response) without secondary P_Max augmentation, and cardiomyocyte stretch did not affect intracellular Ca²⁺ levels. Hearts of transgenic mice with cardiac-specific TRPV4 expression exhibited P_Max similar to 3- to 12-month control mice prior to and immediately following preload elevation but displayed secondary P_Max 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.

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.