Abstract 20432: Phosphorylated Cardiac Myosin Binding Protein-C Alters Signaling Response to Improve Survival in Heart Failure With Reduced Ejection Fraction
Introduction: Cardiac myosin binding protein-C (cMyBP-C) is a heart muscle thick filament protein. Phosphorylated cMyBP-C increases cross-bridge cycling rate to enhance contractility and lusitropy.
Hypothesis: Phosphorylated cMyBP-C can mitigate heart failure with reduced ejection fraction (HFrEF), which have both systolic and diastolic dysfunctions.
Methods: We tested our idea by challenging WT equivalent cMyBP-C(tWT), phosphorylation deficient cMyBP-C(t3SA):S273A/S282A/S302A, and phosphorylation mimetic cMyBP-C(t3SD):S273D/S282D/S302D mouse models with trans-aortic constriction (TAC) to induce HFrEF.
Results: Increasing phosphorylation levels of cMyBP-C provided 5-week survival advantage (t3SA 40/69 58%, tWT 35/46 76%, t3SD 39/44 89%, p=0.001). We then examined cardiac function and signaling cascades to elucidate contributory mechanisms at the 3rd week, where survival curves separated. The phosphorylation mimetic t3SD model showed better preservation of diastolic function by echocardiography (smaller E/e’ at early diastole, E=peak blood inflow velocity Doppler, e’=peak myocardial relaxation velocity tissue Doppler). Phosphorylated protein staining showed that TAC increased phosphorylation of cMyBP-C in t3SA hearts. Since known PKA sites have been mutated in t3SA, this new finding indicates that existence of non-PKA sites play significant roles. TAC uniquely caused [t3SA]: increased cardiac troponin-I phosphorylation, decreased regulated light chain phosphorylation, decreased SERCA2a with decreased phospholamban phosphorylation, decreased PKA phosphorylation, increased CaMK2d phosphorylation, decreased Akt-308 phosphorylation, and increased p38 phosphorylation, [t3SD]: decreased CaMK2d and JNK phosphorylation, [tWT]: decreased ERK phosphorylation.
Conclusions: Thus, in addition to better preservation of diastolic function, phosphorylated cMyBP-C altered signaling response to TAC to improve survival.
Author Disclosures: Y. Liu: None. P.C. Rosas: None. D.T. Kidwell: None. C.W. Tong: None.
- © 2016 by American Heart Association, Inc.