Author + information
- Dhriti Mukhopadhyay,
- Yang Liu,
- Mohamed Abdalla,
- Himakarnika Alluri,
- Candice Thomas,
- Rajesh Kumar,
- Chad Warren,
- Patricia Powers,
- Kenneth Baker,
- Richard L. Moss,
- R. John Solaro and
- Carl Tong
Cardiac myosin-binding protein-C (MyBPC3), a thick filament protein that inhibits myosin-actin interaction to slow cross-bridge cycling, has been implicated in diastolic dysfunction. MyBPC3 phosphorylation releases this inhibition; thus, we hypothesize that MyBPC3 phosphorylation promotes lusitropy.
We expressed normally phosphorylatable MyBPC3WT (tWT), phosphorylation mimetic MyBPC33SD (t3SD), and non-phosphorylatable MyBPC33SA (t3SA) onto MyBPC3(−/-) background to test our hypothesis.
t3SA hearts showed preserved ejection fraction, elevated peak blood flow/myocardial relaxation velocity ratio (E/Ea), and depressed dPmin/dPmax by echocardiography and direct pressure measurements. Furthermore, t3SA mice ran shorter distances, had increased lung/body and heart/body weight ratios, and elevated BNP levels. Conversely, t3SD hearts demonstrated strikingly enhanced relaxation. There were no post-translational modification differences on all other regulatory contractile proteins among all mouse lines by 2D-DIGE analyses.
t3SA resembles heart failure with preserved ejection fraction (HFpEF) while t3SD demonstrated enhanced lusitropy. Thus, MyBPC3 phosphorylation is a critical modulator of diastolic function and a promising therapy for HFpEF.
|Mean ± SE|
|*p<0.05 vs. tWT||tWT||t3SA||t3SD|
|#p<0.05 vs. t3SD|
|BNP/GAPDH mRNA ratio||n=8||n=8||n=6|
|Voluntary Running – week 4 daily average (km/day)||n=10||n=14||n=12|
|Lung/Body weight (mg/g)||n=9||n=9||n=14|
|Heart/Body weight (mg/g)||n=9||n=9||n=14|
|Ejection Fraction (%)||n=12||n=12||n=12|
|Isovolumetric Relaxation Time (ms)||20.9±0.8||34.0±1.3*#||18.3±1.1|
Poster Sessions, Expo North
Saturday, March 09, 2013, 3:45 p.m.-4:30 p.m.
Session Title: Novel Therapeutic Targets in Hearts Failure
Abstract Category: 16. Heart Failure: Basic
Presentation Number: 1176-295
- 2013 American College of Cardiology Foundation