Abstract 17970: Cardiac Myosin Binding Protein-C Phosphorylation Mitigates Pressure-Overload Induced Heart Failure
Cardiac myosin binding protein-C (MYBPC3) is a muscle thick filament protein that inhibits actin-myosin cross-bridge interaction. Phosphorylation can release MYBPC3 inhibition to improve cardiac contractility and lusitropy. MYBPC3 phosphorylation levels are decreased in heart failure. Thus, we hypothesize that MYBPC3 phosphorylation can mitigate pressure overload induced heart failure. We tested our idea by using severe trans-aortic constriction (TAC) induced pressure overload to challenge mouse models of phosphorylation deficient MYBPC3(S273A, S282A, S302A)-MYBPC3(t3SA), phosphorylation mimetic MYBPC3 (S273D, S282D, S302D)-MYBPC3(t3SD), and WT-control MYBPC3(tWT) of MYBPC3. Prior to TAC or sham surgery, MYBPC3(t3SA) hearts exhibited hypertrophy, predominantly diastolic dysfunction (elevated E/Ea ratio, E=mitral blood flow velocity Doppler, Ea= myocardial relaxation velocity tissue Doppler), preserved ejection fraction (EF>50%), and elevated Akt activation. In contrast, pre-surgery MYBPC3(t3SD) hearts demonstrated enhanced diastolic function (smaller E/Ea). At TAC+3weeks, MYBPC3(t3SA) showed depressed EF and increased E/Ea only in comparison to MYBPC3(t3SD). At TAC+5weeks, MYBPC3(t3SA) deteriorated further to exhibit reduced EF, increased E/Ea, and left ventricular dilation vs. MYBPC3(tWT) and MYBPC3(t3SD). Furthermore, MYBPC3(t3SA) demonstrated increased TAC+5 weeks mortality. Thus, we conclude that loss of MYBPC3 phosphorylation directly contributed to heart failure and the combination of (S273-P, S282-P, S302-P) improved preservation of cardiac function.
- © 2013 by American Heart Association, Inc.