Abstract 223: Troponin I Tyrosine Phosphorylation Modulation of Cardiac Function

Heart failure results in depressed contraction and slowed relaxation, both of which limit heart function and contribute to the progression of heart disease. Currently there is no chronic therapy to accelerate relaxation and reverse the diastolic dysfunction present in heart failure. Myocardial relaxation is regulated by serine/threonine phosphorylation of key regulatory proteins. Tyrosine (Tyr) specific kinases are expressed in the heart but the Tyr phosphorylation of regulatory proteins to modulate heart function has not been demonstrated. To investigate the effects of Tyr kinase phosphorylation on cardiac contraction we employed a novel cell penetrating peptide to deliver a direct Tyr kinase activator into isolated adult myocytes. Results demonstrate Tyr kinases activation increases Tyr phosphorylation of the regulatory protein troponin I (TnI) at Tyr26. We have demonstrated that TnI Tyr26 phosphorylation is beneficial to cardiac health by decreasing calcium sensitivity and accelerating myofilament deactivation (key determinants in accelerating myocardial relaxation) and that TnI Tyr26 phosphorylation undergoes functional integration with TnI Ser23/24 resulting in further accelerated calcium dissociation (accelerated relaxation) without further decreased calcium sensitivity (no further depression of contraction). We now demonstrate TnI Tyr26 also undergoes novel signaling integration with TnI Ser23/24 phosphorylation increasing the rate of Tyr kinase mediated Tyr26 phosphorylation. For the first time we demonstrate tyrosine kinase phosphorylation of TnI at Tyr26 modulates cardiac function resulting in accelerated relaxation. Increasing TnI Tyr26 phosphorylation may therefore serve as a novel targeted mechanism for future therapeutic development to accelerate depressed myocardial relaxation and improve diastolic dysfunction in heart failure.