Abstract 15299: TRPC6 is a cGMP-Regulated Cardiomyocyte Mechano-Sensor Amplified by Dystrophin Deficiency
Background: The heart adapts to mechanical stress by augmenting myocyte stretch-mediated intracellular calcium, with a subsequent increase in contractility. This otherwise normal response can trigger tissue damage in disorders such as Duchenne Muscular Dystrophy (DMD); thus, defining its mechanisms has clinical importance. We tested the hypothesis that transient receptor potential canonical (TRPC) channels are responsible, and can be suppressed by protein kinase G (PKG) modulation.
Methods and Results: Contracting isolated trabeculae and myocytes from control or TRPC1, 3, or 6 knock-out mice were subjected to isometric or auxotonic stress. Deletion of either TRPC1 or TRPC6 but not TRPC3 suppressed contractility rise following stress application. Incubation with cGMP analog to stimulate PKG eliminated contractility augmentation after stress in controls but not muscles or cells lacking TRPC6. This identified TRPC6 as the primary target for PKG modulation. In the mdx/utrophin+/- mouse, a model of DMD that displayed 3-fold higher TRPC6 expression but unaltered TRPC1 expression, stress-stimulated contractility more than doubled, and 60% of cells developed arrhythmia. PKG activation or direct TRPC6 inhibition suppressed both arrhythmia and augmented contractility. Chronic stimulation of PKG by inhibition of phosphodiesterase type 5A inhibition also resulted in normalization of the abnormal contractility response to stress, while also suppressing in vivo cardiac hypertrophy and dysfunction over time.
Conclusions: TRPC1 and TRPC6 are the mechano-sensors responsible for contractility enhancement to stress. In dystrophin deficiency, TRPC6 is enhanced and destabilized, augmenting stress-modulated force and arrhythmia. This pathologically amplified response is potently suppressed by cGMP/PKG in a TRPC6-dependent manner, presenting a novel avenue for treating hyperactive mechano-sensing and associated arrhythmia in the diseased heart.
- © 2013 by American Heart Association, Inc.