Abstract 437: Tyrosine Phosphorylation: Regulator of Cardiac Contraction

Abstract

Myocardial contractile function is depressed in heart failure. Contractile function of the normal and failing heart is in part determined by kinase mediated serine/threonine phosphorylation. While non-receptor tyrosine specific kinases are expressed in the heart and their activity is increased in disease, the role of tyrosine kinase signaling to modulate cardiac contraction is unknown. Previous work demonstrated the cardiac contractile regulatory protein troponin I (TnI) is phosphorylated at tyrosine 26 (Tyr26). Subsequently, we demonstrated TnI Tyr26 phosphorylation alters myofilament function thereby identifying the first tyrosine phosphorylation to directly modulate cardiac contraction. The role of TnI Tyr26 phosphorylation in the normal or diseased heart and the signaling pathways responsible for its phosphorylation are unknown. To identify the kinase responsible for TnI Tyr26 phosphorylation and its effect on in vivo heart function, we generated a novel tyrosine kinase activator and a TnI Tyr26 phosphorylation (Tg Y26E) mouse. Biochemical kinase assays and kinase activation in ventricular myocytes identify Src family kinases as sufficient to induce TnI Tyr26 phosphorylation. Tg Y26E mice exhibit decreased myofilament calcium sensitivity and accelerated relaxation. Finally, we demonstrate TnI Tyr26 phosphorylation is increased during in vivo myocardial ischemia when Src family tyrosine kinases are also activated. Together these data support targeting Src family tyrosine kinase and TnI Tyr26 phosphorylation to improve heart function in myocardial ischemia and the failing heart.