| First Author | Chung HS | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 50 | Pages | E10763-E10771 |
| PubMed ID | 29187535 | Mgi Jnum | J:256511 |
| Mgi Id | MGI:6103290 | Doi | 10.1073/pnas.1712623114 |
| Citation | Chung HS, et al. (2017) Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 114(50):E10763-E10771 |
| abstractText | Duchenne muscular dystrophy (DMD) is an X-linked disorder with dystrophin loss that results in skeletal and cardiac muscle weakening and early death. Loss of the dystrophin-sarcoglycan complex delocalizes nitric oxide synthase (NOS) to alter its signaling, and augments mechanosensitive intracellular Ca(2+) influx. The latter has been coupled to hyperactivation of the nonselective cation channel, transient receptor potential canonical channel 6 (Trpc6), in isolated myocytes. As Ca(2+) also activates NOS, we hypothesized that Trpc6 would help to mediate nitric oxide (NO) dysregulation and that this would be manifest in increased myocardial S-nitrosylation, a posttranslational modification increasingly implicated in neurodegenerative, inflammatory, and muscle disease. Using a recently developed dual-labeling proteomic strategy, we identified 1,276 S-nitrosylated cysteine residues [S-nitrosothiol (SNO)] on 491 proteins in resting hearts from a mouse model of DMD (dmd(mdx):utrn(+/-)). These largely consisted of mitochondrial proteins, metabolic regulators, and sarcomeric proteins, with 80% of them also modified in wild type (WT). S-nitrosylation levels, however, were increased in DMD. Genetic deletion of Trpc6 in this model (dmd(mdx):utrn(+/-):trpc6(-/-)) reversed approximately 70% of these changes. Trpc6 deletion also ameliorated left ventricular dilation, improved cardiac function, and tended to reduce fibrosis. Furthermore, under catecholamine stimulation, which also increases NO synthesis and intracellular Ca(2+) along with cardiac workload, the hypernitrosylated state remained as it did at baseline. However, the impact of Trpc6 deletion on the SNO proteome became less marked. These findings reveal a role for Trpc6-mediated hypernitrosylation in dmd(mdx):utrn(+/-) mice and support accumulating evidence that implicates nitrosative stress in cardiac and muscle disease. |
