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An Exercise Mimetic That Targets Nitroso-Redox Balance as a Therapeutic for Heart Disease

  • Vikram Shettigar
  • Mark T. ZioloEmail author
Chapter

Abstract

Numerous investigations performed over the last few decades clearly indicate that exercise leads to adaptations of the heart resulting in improved function and protection against various cardiovascular diseases (CVD) and is a powerful rehabilitation tool for cardiovascular patients. However, attaining the required intensity of exercise for these cardiac adaptations may not be possible due to numerous constraints such as physical inability, mental unwillingness, stress, etc. Thus, an exercise mimetic drug (i.e., a drug that can mimic the effects of exercise at the cellular level) can be a novel therapeutic approach for cardiovascular patients. An increase in reactive oxygen species (ROS), known as oxidative stress, in the cardiomyocyte and vasculature initiates adverse signaling mechanisms causing numerous detrimental effects. This oxidative stress is a key contributor to the development of CVD. Unfortunately, antioxidant therapy has shown little clinical benefit. In addition to the increased ROS, there is also a concurrent reduction in nitric oxide (NO) levels in CVD. Studies have shown that NO signaling has a protective effect in the cardiomyocyte and vasculature. Contrary to CVD, exercise decreases ROS levels (i.e., antioxidant effect) and increases NO production. Recent studies have shown that ROS and NO do not function independently but work in tandem, known as the nitroso-redox balance, and help clarify the failure of antioxidant therapies. The nitroso-redox balance is critical to maintain a healthy cardiac state. In CVD, there is a detrimental shift in the nitroso-redox balance, while exercise results in a positive shift of this balance. A possible exercise mimetic may be a drug that restores this nitroso-redox balance. We have developed such a drug (EMEPO) that can simultaneously decrease ROS levels and increase NO levels. Studies at the cellular level and pre-clinical models of CVD have demonstrated that EMEPO, by restoring the nitroso-redox balance, improved cardiomyocyte and heart function. Thus, mimicking exercise effects on the heart via EMEPO may be a paradigm-shifting therapeutic strategy.

Keywords

Exercise Nitric oxide Reactive oxygen species Excitation-contraction coupling 

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Physiology and Cell Biology, Davis Heart and Lung Research InstituteThe Ohio State UniversityColumbusUSA

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