Abstract 5: Restoring Nitroso-Redox Balance as a Therapeutic Approach for Cardiovascular Disease
| Autor: | Vikram Shettigar, Honglan Wang, Bo Zhang, Steve R Roof, Paul M Janssen, Jonathan P Davis, Richard J Gumina, Brandon J Biesiadecki, Frederick A Villamena, Mark T Ziolo |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Circulation Research. 121 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/res.121.suppl_1.5 |
| Popis: | Anti-oxidant therapy has been an immense clinical disappointment for the treatment of cardiomyopathies. Concurrently with the increase in reactive oxygen species (ROS), there is also a decrease in cardiac levels of nitric oxide (NO), resulting in a nitroso-redox imbalance not addressed by anti-oxidant treatment alone. Key modulators of cardiac function are sensitive to the nitroso-redox balance such as kinases and phosphatases. Thus, along with changes in protein oxidation and/or S-nitrosylation levels, the nitroso-redox imbalance also alters protein phosphorylation. We developed a unique and novel compound (EMEPO) that can correct the nitroso-redox imbalance by simultaneously scavenging ROS and producing NO. We hypothesized that EMEPO is a novel agent that will ameliorate cardiac dysfunction by reestablishing the proper protein post-translational modifications. We demonstrated the efficacy of EMEPO in two cardiac models of nitroso-redox imbalance; a genetic model (NOS1 -/- ) and a disease model- murine myocardial infraction (MI). Both models displayed nitroso-redox imbalance with systolic and diastolic dysfunction. EMEPO treatment had a much greater effect than anti-oxidant treatment alone in palliating the cardiac dysfunction. A major contributor to these dysfunctions observed in cardiomyopathies is altered ryanodine receptor (RyR) activity. EMEPO was able to restore RyR activity and each aberrant post-translational modification (oxidation, S-nitrosylation, and phosphorylation). We believe these EMEPO-induced changes in RyR will occur in many proteins that orchestrate signaling networks and function. Our data highly suggest that simultaneously restoring both ROS and NO levels (i.e., correcting the nitroso-redox imbalance) is a promising therapeutic approach for MI and heart failure patients. Our first designed nitroso-redox balancer, EMEPO, shows great potential as a novel strategy for the treatment of heart disease. |
| Databáze: | OpenAIRE |
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