Abstract 253: Pharmacological and Genetic Inhibition of Transient Receptor Potential Canonical 6 (TRPC6) as a Novel Treatment for Heart Failure and Duchenne Muscular Dystrophy (DMD) Pharmacological and Genetic Inhibition of Transient Receptor Potential Canonical 6 (TRPC6) as a Novel Treatment for Heart Failure and Duchenne Muscular Dystrophy (DMD)

• Published in: Circulation research Vol. 125; no. Suppl_1
• Main Authors: Lin, Brian L, Mishra, Sumita, Muller, Grace K, Bedja, Djahida, Zhu, Guangshuo, Yang, Jinying, Anderson, Mark E, Pullen, Steve S, Kass, David A
• Format: Journal Article
• Language: English
• Published: 02.08.2019
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.125.suppl_1.253

Abstract only Intro: Duchenne muscular dystrophy (DMD) patients suffer from spinal deformities (scoliosis and kyphosis) and die prematurely in their thirties, mostly due to heart disease. DMD is caused by the lack of the dystrophin protein, but calcium overload contributes to pathology as a secondary insult. Inhibiting hyperactive calcium channels in DMD, such as TRPC6, is a novel therapeutic strategy for treating DMD, and we test the efficacy of pharmacological and genetic TRPC6 inhibition in vivo . Therefore, my objectives are: 1) determine the efficacy of chronic pharmacological TRPC6 inhibition in heart disease 2) determine the therapeutic efficacy of genetic TRPC6 inhibition in DMD and 3) identify novel mechanisms of TRPC6 hyperactivity. Results: 1) Using pressure-overloaded mice as our model of heart disease, we applied the first and only-known TRPC6 inhibitor (BI 749327, 30 mg/kg/day) that is both specific and bioavailable. Chronic pharmacological TRPC6 inhibition blunted a pathological calcineurin/NFAT-TRPC6 feedforward signaling pathway in vivo , resulting in improved fractional shortening, normalized cardiac hemodynamics, and potently reduced fibrotic signaling and fibrosis. 2) We generated dystrophin-utrophin-deficient mice, or double-knock-out (DKO) mice, a severe model of DMD that exhibits muscle weakness, spinal deformities, and premature death at ~8 weeks of age. We also generated dystrophin-utrophin-TRPC6-deficient mice, or triple-knock-out (TKO) mice, which exhibited dramatically improved kyphosis, striated muscle function, and nearly three-fold improvement in lifespan. 3) We demonstrate CaMKII mediates TRPC6-mediated contractility combining a custom cardiomyocyte stretch assay with pharmacological and genetic inhibition of TRPC6 and CaMKII. Conclusion: TRPC6 inhibition potently reduces fibrosis in heart disease, and dramatically improves life expectancy in DMD. CaMKII is a novel TRPC6-activating kinase, necessary for TRPC6-mediated mechanosensitive activation and force response. The striking therapeutic effects of TRPC6 inhibition in disease may be due to interruption of a kinase imbalance in which CaMKII hyperactivates TRPC6. Future studies will determine the efficacy of pharmacological TRPC6 inhibition in DMD.