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Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):E10763-E10771. doi: 10.1073/pnas.1712623114. Epub 2017 Nov 29.

Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy.

Author information

1
Advanced Clinical BioSystems Research Institute, Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048.
2
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
3
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; dkass1@jhmi.edu jennifer.vaneyk@cshs.org.
4
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
5
Advanced Clinical BioSystems Research Institute, Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048; dkass1@jhmi.edu jennifer.vaneyk@cshs.org.

Abstract

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 Ca2+ influx. The latter has been coupled to hyperactivation of the nonselective cation channel, transient receptor potential canonical channel 6 (Trpc6), in isolated myocytes. As Ca2+ 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 (dmdmdx: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 (dmdmdx:utrn+/-:trpc6-/-) reversed ∼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 Ca2+ 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 dmdmdx:utrn+/- mice and support accumulating evidence that implicates nitrosative stress in cardiac and muscle disease.

KEYWORDS:

Duchenne muscular dystrophy; Trpc6; mass spectrometry; nitric oxide synthase signaling; protein S-nitrosylation

PMID:
29187535
PMCID:
PMC5740634
DOI:
10.1073/pnas.1712623114
[Indexed for MEDLINE]
Free PMC Article

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