Abstract 250: Canonical Transient Receptor Potential Channel 6 Ameliorates Increased Cardiac S-nitrosylation in Duchenne Muscular Dystrophy
| Autor: | Grace E Kim, Heaseung S Chung, Ronald J Holewinski, Guangshuo Zhu, Vidya Venkatraman, Djahida Bedja, Jennifer E Van Eyk, David A Kass |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Circulation Research. 121 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/res.121.suppl_1.250 |
| Popis: | Duchenne muscular dystrophy (DMD) is an X-linked disorder that markedly weakens skeletal and cardiac muscle to cause early death. Its elimination of dystrophin disrupts nitric oxide (NO) signaling and amplifies intracellular Ca 2+ responses to mechanical load. We have shown the latter is linked to hyperstimulated transient receptor potential canonical 6 (TRPC6) cation channels. As Ca 2+ also activates NO synthase, we hypothesized TRPC6 couples to redox-dependent nitrosative stress to broadly impact protein S-nitrosylation (SNO). Using an unbiased, dual-labeling proteomic strategy we identified 1276 SNO sites on 491 proteins in DMD hearts (dystrophin/utrophin +/- ), of which 102 sites among 69 proteins were unique to DMD. Many of the targeted proteins were mitochondrial or metabolic regulators and sarcomere proteins - including titin, myosin binding protein-C, α-myosin heavy-chain, and tropomyosin α1 - that were hyper-nitrosylated. A key redox regulator peroxiredoxin1 was also hyper-nitrosylated at Cys173, a site previously shown to be a requisite regulator of its dimerization and enzymatic activity. DMD mice were then crossed into a Trpc6 -/- background, and proteomic analysis now found 70% of SNO targeted residues in DMD were reversed towards normal (p2 ). Trpc6 deletion improved left ventricular dilation (13.7±1.2mm, 22.4±3.9mm, 15.3±2.3mm; p-/- respectively (1-way ANOVA), and reversed pro-fibrotic gene activation (connective tissue growth factor, fibronectin1 and osteopontin). These results provide the first broad-based SNO analysis of the DMD heart, and support linkage between abnormal calcium via TRPC6, nitrosative stress and cardiac disease. |
| Databáze: | OpenAIRE |
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