Heart failure accounts for approximately 1 out of every 7 deaths in America. Heart failure results in depressed cardiac systolic contraction and slowed diastolic relaxation, both of which limit heart function and contribute to disease. Currently there is no therapy to specifically increase myocardial relaxation and improve function of the failing heart. Myocardial relaxation is mediated by serine/threonine phosphorylation. We have demonstrated the first tyrosine (Try) phosphorylation identified in the heart directly modulates cardiac muscle function. Our data demonstrates specific activation of Tyr kinases in living myocardium increase Tyr phosphorylation on the regulatory protein troponin I (TnI). We further demonstrate increased TnI Tyr phosphorylation beneficially alters rodent and human cardiac muscle contractile properties key to accelerating myocardial relaxation. These findings support increasing TnI Tyr phosphorylation in the failing heart as a potential novel target to improve diastolic dysfunction in heart failure. In this proposal we will employ novel genetic and pharmacological techniques to define the beneficial accelerated relaxation effects of TnI Tyr phosphorylation as a mechanism improve in vivo diastolic function of the normal and failing heart and improve survival in heart failure. In addition, we will begin to translate these beneficial effects of TnI Tyr phosphorylation towards the future development of a targeted therapy for human heart failure by establishing the relaxation effects of increasing TnI Tyr phosphorylation in non-failing and failing living human myocardium. The specific outcome of this proposal is to establish the beneficial effects of TnI Tyr phosphorylation on in vivo heart function of the failing heart and to translate these functional effects into the human myocardium to establish TnI Tyr phosphorylation as a target for future heart failure therapy development.

Public Health Relevance

Heart function is depressed in the failing heart as a result of slowed diastolic myocardial relaxation with no current therapy to improve this impaired relaxation. We have defined a novel mechanism to accelerate myocardial relaxation that this study will establish as beneficial to improve heart function in diseased animal models and living human heart muscle. The data generated in this proposal will serve as critical information towards developing future therapies to accelerate myocardial relaxation, improve diastolic dysfunction and overall function of the failing heart.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Adhikari, Bishow B
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Ohio State University
Schools of Medicine
United States
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