Abstract 13462: Cardiac Myosin Binding Protein-C Phosphorylation is Essential for Normal Diastolic Function
Heart failure with preserved ejection fraction (HFpEF) is a primarily diastolic dysfunction disease for which there is no effective treatment. Cardiac myosin binding protein-C (MyBPC3) is a thick filament accessory protein which slows cross-bridge cycling when unphosphorylated. We hypothesize that phosphorylation of MyBPC3 releases this depression of function to enhance heart muscle’s ability to relax (i.e., positive lusitropy). We expressed phosphorylation-mimetic (t3SD=S273D/S282D/S302D), wild type (tWT), and non-phosphorylatable (t3SA=S273A/S282A/S302A) MyBPC3 on the null MyBPC3(-/-) background at similar expression levels to create mouse models to test our hypothesis. MyBPC3(t3SD) hearts exhibit enhanced lusitropy on echocardiography evident as faster tissue doppler myocardial relaxation velocity Ea and smaller blood flow doppler E/Ea ratio. Conversely, MyBPC3(t3SA) mice resemble HFpEF as seen by preserved ejection fraction, significant diastolic dysfunction (i.e., elevated E/Ea), shorter 14-day voluntary running distances, increased brain natriuretic levels, and increased lung/body weight ratio. 2-dimensional differential gel-electrophoresis verified that t3SA and t3SD mutations did not change phosphorylation levels of troponin-I, tropomyosin, troponin-T, or myosin light chain-2. Furthermore, severe trans-aortic constriction (gradient > 70 mmHg) caused less diastolic dysfunction in MyBPC3(t3SD) hearts. Thus, we conclude that MyBPC3 phosphorylation is essential for normal diastolic function and provides a potential target for treating diastolic dysfunction. .
- © 2012 by American Heart Association, Inc.