Nitric oxide inhibits dystrophin proteolysis by coxsackieviral protease 2A through S-nitrosylation: A protective mechanism against enteroviral cardiomyopathy

Infection with enteroviruses like coxsackievirus B3 (CVB3) as well as genetic dystrophin deficiency can cause dilated cardiomyopathy. We recently identified cleavage and functional impairment of dystrophin by the viral protease 2A during CVB3-infection as a molecular mechanism that may contribute to...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2000-10, Vol.102 (18), p.2276-2281
Main Authors: BADORFF, Cornet, FICHTLSCHERER, Birgit, RHOADS, Robert E, ZEIHER, Andreas M, MUELSCH, Alexander, DIMMELER, Stefanie, KNOWLTON, Kirk U
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blotting, Western
Cardiomyopathy, Dilated - metabolism
Cardiomyopathy, Dilated - prevention & control
Catalytic Domain - drug effects
COS Cells
Cysteine - metabolism
Cysteine Endopeptidases - drug effects
Cysteine Endopeptidases - genetics
Cysteine Endopeptidases - metabolism
Densitometry
Dystrophin - metabolism
Enterovirus Infections - metabolism
Enterovirus Infections - prevention & control
Enzyme Activation - drug effects
Enzyme Inhibitors - pharmacology
HeLa Cells
Human viral diseases
Humans
Hydrazines - pharmacology
Infectious diseases
Medical sciences
Mice
Nitric Oxide - metabolism
Nitric Oxide - pharmacology
Nitric Oxide Donors - pharmacology
Nitrogen Oxides
Penicillamine - analogs & derivatives
Penicillamine - pharmacology
Peptide Hydrolases - metabolism
S-Nitroso-N-Acetylpenicillamine
Spermine - analogs & derivatives
Spermine - pharmacology
Sulfhydryl Compounds - metabolism
Viral cardiopathies
Viral diseases
Viral Fusion Proteins - genetics
Viral Proteins
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Summary:Infection with enteroviruses like coxsackievirus B3 (CVB3) as well as genetic dystrophin deficiency can cause dilated cardiomyopathy. We recently identified cleavage and functional impairment of dystrophin by the viral protease 2A during CVB3-infection as a molecular mechanism that may contribute to the pathogenesis of enterovirus-induced cardiomyopathy. Nitric oxide (NO) is elevated in human dilated cardiomyopathy, but the relevance of this finding is unknown. In mice, NO inhibits CVB3 myocarditis. Therefore, we investigated the effects of NO on the coxsackieviral protease 2A. In vitro, NO donors like PAPA-NONOate inhibited the cleavage of human and mouse dystrophin by recombinant coxsackievirus B protease 2A in a dose-dependent manner (IC(50), 51 micromol/L). In CVB3-infected HeLa cells, addition of the NO donor SNAP inhibited protease 2A catalytic activity on dystrophin. Because this inhibitory effect was reversed by the thiol-protecting agent DTT, we investigated whether NO S:-nitrosylates the protease 2A. In vitro, NO nitrosylated the active-site cysteine (C110) of the coxsackieviral protease 2A, as demonstrated by site-directed mutagenesis. Within living COS-7 cells, SNAP-induced S:-nitrosylation of this site was confirmed with electron spin resonance spectroscopy. These data demonstrate inactivation of a coxsackieviral protease 2A by NO through active-cysteine S:-nitrosylation in vitro and intracellularly. Given that the enteroviral protease 2A cleaves mouse and human dystrophin, NO may be protective in human heart failure with an underlying enteroviral pathogenesis through inhibition of dystrophin proteolysis.
ISSN:0009-7322
1524-4539
DOI:10.1161/01.CIR.102.18.2276