Nitric Oxide Inhibits Dystrophin Proteolysis by Coxsackieviral Protease 2A Through
            <i>S</i>
            -Nitrosylation

Badorff, Cornel; Fichtlscherer, Birgit; Rhoads, Robert E.; Zeiher, Andreas M.; Muelsch, Alexander; Dimmeler, Stefanie; Knowlton, Kirk U.

doi:10.1161/01.cir.102.18.2276

Cited by 72 publications

(43 citation statements)

References 42 publications

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“…On the one hand, expression of NO exhibits direct anti-viral effects in CVB3-infected mice by inhibition of a viral proteinase. 29 On the other hand, oxidative stress leads to programmed cell death of cardiomyocytes. 30 Therefore, it is likely that unrestricted NO synthesis by activated macrophages contributes to cardiac tissue damage and needs to be regulated.…”

Section: Discussionmentioning

confidence: 99%

Sustained Nitric Oxide Synthesis Contributes to Immunopathology in Ongoing Myocarditis Attributable to Interleukin-10 Disorders

Szalay

Sauter

Hald

et al. 2006

The American Journal of Pathology

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Ongoing coxsackievirus B3 (CVB3) myocarditis is characterized by persistence of viral RNA and chronic inflammation primarily mediated by macrophages and T cells. Activated macrophages produce anti-viral effector molecules comprising reactive nitrogen intermediates; however, reactive nitrogen intermediates also contribute to host tissue damage. Controlled activation of macrophages depends on interferon (IFN)-␥ and interleukin (IL)-10. To evaluate mechanisms involved in CVB3-induced pathogenesis of myocarditis, we determined the relationship of inducible nitric-oxide synthase (iNOS) mRNA expression with IFN-␥ and IL-10 secretion during CVB3 infection in different mouse strains. We found in susceptible A.BY/SnJ mice that develop ongoing myocarditis, a low and delayed IFN-␥ secretion and highly diminished IL-10 production compared with resistant C57BL/6 mice. Consequently, iNOS mRNA synthesis was delayed but clearly prolonged in susceptible mice. IL-10 gene-deficient mice confirmed the regulatory role of IL-10 in the outcome of CVB3 myocarditis. These mice did not establish a persistent cardiac infection and revealed IFN-␥ secretion kinetics similar to resistant mice but showed a slightly elongated cardiac iNOS mRNA expression resulting in extended myocarditis. We conclude that coordinated secretion of IFN-␥ and IL-10 is crucial for the effective resolution of CVB3 myocarditis. Moreover, lack of regulatory IL-10 leads to uncontrolled iNOS mRNA production, thus contributing to ongoing myocardial injury. The natural course of human enterovirus myocarditis varies from a subclinical infection to fulminant acute myocarditis with congestive heart failure. Susceptible patients may develop a chronic inflammatory heart disease leading to dilated cardiomyopathy, which in its end stage can be treated effectively only by heart transplantation.

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Section: Discussionmentioning

confidence: 99%

Sustained Nitric Oxide Synthesis Contributes to Immunopathology in Ongoing Myocarditis Attributable to Interleukin-10 Disorders

Szalay

Sauter

Hald

et al. 2006

The American Journal of Pathology

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“…13 Pro cleavage buffer as described. 11 The activity of 2A Pro was measured by a fluorometric assay based on the specific hydrolysis of synthetic peptide substrate Ac-LSTT-AFC.…”

Section: Assay For 2a Pro Activitymentioning

confidence: 99%

Inducible Cardiac-Restricted Expression of Enteroviral Protease 2A Is Sufficient to Induce Dilated Cardiomyopathy

et al. 2007

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Background-Enterovirus infection is a cause of cardiomyopathy. We previously demonstrated that enteroviral protease 2A directly cleaves the cytoskeletal protein dystrophin. However, the direct effect of protease 2A in enteroviral cardiomyopathy is less clear because other viral proteins are also expressed with viral infection. Methods and Results-A transgenic mouse with inducible cardiac-restricted expression of enteroviral protease 2A was generated. In the transgenic mouse, a tamoxifen-regulated Cre-loxP system, MerCreMer (MCM), was used to induce genetic recombination in cardiac myocytes, which led to protease 2A expression. Protease 2A and MCM double transgenic (2AxMCM) mice were treated with tamoxifen; the controls included 2AxMCM mice treated with diluents for tamoxifen and tamoxifen-treated MCM littermates. Protease 2A activity was significantly induced after tamoxifen in the 2AxMCM mice compared with controls. Echocardiographic analysis demonstrated an increase in left ventricular end-diastolic and end-systolic chamber size, with decreased fractional shortening in tamoxifen-treated 2AxMCM mice.There was an increase in heart weight-to-body weight ratio in 2AxMCM mice treated with tamoxifen. Only a small increase in interstitial fibrosis and inflammation was found in tamoxifen-treated 2AxMCM mice; however, ultrastructural analysis demonstrated myofibrillar collapse with abnormalities of intercalated discs and sarcolemmal membranes. Evans blue dye-positive myocytes with disruption of dystrophin were present in 2AxMCM mice treated with tamoxifen. Disruption of dystrophin was also found in cultured myocytes isolated from 2AxMCM mice with Cre in the nucleus. Conclusions-Protease

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“…All NO donor stock solutions were made fresh right before the experiment and diluted into cell culture together with apoptosis-inducing agents STS or Camp, except for DPTA NONOate, which was diluted into culture 30 mins before the addition of STS or Camp. The concentrations of NO donors used were determined based on dose-response experiments and were in the range of those used by others (Badorff et al, 2000;Chen et al, 2001;Kim et al, 2000;Reynaert et al, 2004). However, in cell cultures, the concentration of NO to which the cells are exposed is much smaller than that of the NO donor added to the culture and is likely to be even smaller in the cytoplasm when NO reaches its intracellular targets (Beltran et al, 2000;Kindler et al, 2003).…”

Section: Nitric Oxide Donorsmentioning

confidence: 99%

Nitric Oxide Inhibits Caspase Activation and Apoptotic Morphology but Does Not Rescue Neuronal Death

Zhou

Qian

Iadecola

2005

J Cereb Blood Flow Metab

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Nitric oxide (NO) has been shown to inhibit apoptotic cell death by S-nitrosylation of the catalyticsite cysteine residue of caspases. However, it is not clear whether in neurons NO-mediated caspase inactivation leads to improved cell survival. To address this issue, we studied the effect of NO donors on caspase activity and cell survival in cortical neuronal culture treated with the apoptosis inducer staurosporine (STS) and camptothecin. In parallel, cell viability was assessed by the MTS assay and MAP2 staining. We found that NO donors ((7)-S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione, and NONOates) dose-dependently inhibited caspase-3 and -9 activity induced by STS and camptothecin. The reduction in caspase-3 activity was, in large part, because of the blockage of the proteolytic conversion of pro-caspase-3 to active caspase-3. NO donors also inhibited the appearance of the classical apoptotic nuclear morphology. However, inhibition of both caspase activity and apoptotic morphology was not associated with enhancement of cell viability. Thus, inhibition of caspase and apoptotic morphology by NO donors does not improve neuronal survival. The data suggest that inhibition of caspase by NO unmasks a caspase-independent form of cell death. A better understanding of this form of cell death may provide new strategies for neuroprotection in neuropathologies, such as ischemic brain injury, associated with apoptosis.

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Nitric Oxide Inhibits Dystrophin Proteolysis by Coxsackieviral Protease 2A Through S -Nitrosylation

Cited by 72 publications

References 42 publications

Sustained Nitric Oxide Synthesis Contributes to Immunopathology in Ongoing Myocarditis Attributable to Interleukin-10 Disorders

Sustained Nitric Oxide Synthesis Contributes to Immunopathology in Ongoing Myocarditis Attributable to Interleukin-10 Disorders

Inducible Cardiac-Restricted Expression of Enteroviral Protease 2A Is Sufficient to Induce Dilated Cardiomyopathy

Nitric Oxide Inhibits Caspase Activation and Apoptotic Morphology but Does Not Rescue Neuronal Death

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