Abstract GS108: Troponin I Tyrosine-26 Phosphorylation Improves Relaxation And Is Beneficial During Pathological Diastolic Dysfunction

Abstract

Diastolic dysfunction contributes to disease in both heart failure with preserved and reduced ejection fraction. There are currently no approved therapies to accelerate impaired relaxation for heart failure patients with diastolic dysfunction. A healthy heart can modify its ability to relax through post-translational modifications (e.g., phosphorylation) of myofilament proteins. The inhibitory subunit of the troponin complex, troponin I (TnI), is a key regulator of cardiac contraction and relaxation and is endogenously phosphorylated at Tyr-26. We previously demonstrated that this novel tyrosine phosphorylation decreases calcium sensitivity and accelerates calcium dissociation from troponin C. We therefore hypothesize that increasing TnI Tyr-26 phosphorylation will accelerate relaxation and be beneficial during pathological diastolic dysfunction. To determine the effects of TnI Tyr-26 phosphorylation in vivo , we generated a phospho-mimetic mouse with TnI Tyr-26 mutated to Glu. Structural and functional echocardiography and hemodynamics measurements demonstrate that TnI Tyr-26 phosphorylation accelerates relaxation and increases diastolic function in vivo . To determine the effect of this TnI Tyr-26 phosphorylation mediated acceleration of diastolic function during disease, we performed unilateral nephrectomy with DOCA-salt (neph/DOCA) to induce diastolic dysfunction. Wild-type mice subjected to neph/DOCA develop left ventricular hypertrophy, enlarged left atria, elevated diastolic pressure, and slowed relaxation, indicative of diastolic dysfunction. In contrast with wild-type, TnI Tyr-26 phosphorylation mice subjected to neph/DOCA display normal diastolic function without any cardiac remodeling. Overall, we demonstrate that TnI Tyr-26 phosphorylation inhibits the development of diastolic dysfunction and is therefore a novel mechanism to accelerate myocardial relaxation in vivo.