Targeting Troponin T Regulation to Sustain Cardiac Function in Heart Failure

University Of Illinois At Chicago, Chicago IL

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Abstract

Project Title: Targeting Troponin T Regulation to Sustain Cardiac Function in Heart Failure Project Summary Sufficient blood pumping of the heart depends on ventricular filling and the contractility of cardiac muscle against arterial resistance. Cardiac insufficiency and failure remains a major challenge in the management of cardiovascular diseases. Cardiac muscle contraction and relaxation is regulated by the troponin complex in the sarcomeric thin filament. Troponin consists of three protein subunits: troponin C (TnC), troponin I (TnI), and troponin T (TnT). A restrictive proteolytic cleavage to selectively remove the N-terminal hypervariable region of cardiac TnT (cTnT) occurs as a physiological adaptation to ventricular inotropy-afterload mismatch such as that in acute myocardial ischemia or pressure overload. The N-terminal truncated cTnT (cTnT-ND) remains in the cardiac myofilaments with modified functionality to moderately tune down ventricular peak-systolic velocity, which elongates the time of rapid ejection to sustain stroke volume. Without increasing the peak systolic pressure, this myocardial kinetics-based mechanism also improves the efficiency of cardiac pumping. Based on strong scientific premise, substantial progresses made in the previous funding period of this research project and promising preliminary studies, the proposed new studies focus on investigating the molecular mechanism by which cTnT-ND modulates the kinetics of cardiac myofilament activation and deactivation via the newly identified C-terminal tropomyosin-binding site 3 of TnT for translational applications in treating inotropy-afterload mismatch and diastolic dysfunction of failing hearts. Three new Specific Aims will be pursued: Aim 1 is to characterize how the newly identified tropomyosin-binding site 3 in the C-terminal end segment of TnT functions in tuning the kinetics of cardiac myofilament activation and deactivation. Aim 2 is to assess the effects of cTnT-ND on ventricular systolic and diastolic kinetics in improving cardiac function in heart failures with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Aim 3 is to develop applications of TnT C-terminal peptides in correcting the function of failing hearts. Significance: b-adrenergic blockade has a proven clinical benefit in treating chronic congestive heart failure and prolonging patient life. Without the side effects from systemic decrease in b-adrenergic tone, the cTnT-ND adaptation via the C-terminal tropomyosin-binding site 3 selectively tunes down myocardial peak- systolic velocity to elongate ventricular rapid ejection time and sustain stroke volume against afterload. This myofilament mechanism simulates a therapeutic effect of b-adrenergic blockade and targets a specific kinetic step of the cardiac cycle to improve pumping efficiency in failing hearts. This mechanism can also facilitate relaxation to alleviate myocardial hypertrophy- and over activation-caused diastolic dysfunction in diastolic heart failure. Our studies using integrative multi-level approaches and experimental systems will lay groundwork for ultimately translating this novel molecular mechanism into a new treatment for heart failure.