Abstract 11948: Dominant Negative 14-3-3 Protein Exacerbates Cardiac Dysfunction by Suppressing Cardiac Regeneration After Coronary Artery Ligation in Mice
14-3-3 family members are dimeric phosphoserine-binding proteins participating in signal transduction and checkpoint control pathways. We have previously reported that 14-3-3 protein protects against pressure-overload induced heart failure in mice. However, the role of 14-3-3 protein in myocardial infarction (MI)-induced cardiac dysfunction still remains to be determined. MI was induced by ligating the left anterior descending (LAD) coronary artery in wild type (WT) and cardiac-specific expression of dominant-negative 14-3-3 protein mutant (DN14-3-3) mice. One week later sham surgery; there was no significant difference in cardiac function in WT and DN14-3-3 mice. DN14-3-3 mice with MI showed increased mortality and reduced left ventricular ejection fraction and fractional shortening as compared to WT mice. DN14-3-3 mice showed increased markers of maladaptive cardiac remodeling, cardiac hypertrophy, inflammation, fibrosis and cardiac cell apoptosis as compared to their WT counterparts. Mechanistically, DN14-3-3 mice exhibited increased activation of endoplasmic reticulum (ER) stress. Interestingly, Stem cells marker (C-Kit, ISL-1) expressions were significantly reduced in DN14-3-3 mice with MI when compared to WT mice. In conclusion, depletion of 14-3-3 protein leads to increased mortality associated with increased cardiac dysfunction and adverse cardiac remodeling in mice subjected to MI, possibly, via exacerbation of ER stress and activation of death signaling pathways and suppression of cardiac regeneration. Thus, identification of drugs that can modulate cardiac 14-3-3 protein levels might provide a novel protective therapy for heart failure.
Author Disclosures: R. Amirthalingam Thandavarayan: None. S. Arumugam: None. V. Pitchaimani: None. V. Karuppa Gounder: None. V.V. Giridharan: None. R. Sreedhar: None. M. Harima: None. D. Joladarashi: None. K. Suzuki: None. K. Watanabe: None. P. krishnamurthy: None.
- © 2014 by American Heart Association, Inc.