Abstract 15409: Inactivation of 14-3-3 Protein Exacerbates Cardiac Dysfunction and Reduces Survival in Mice with Myocardial Infarction
Introduction: 14-3-3 family members are dimeric phosphoserine-binding proteins that participate in signal transduction and checkpoint control pathways. For instance, modulations of 14-3-3 protein expression have been reported in animal models of diabetic cardiomyopathy and pressure overload induced heart failure. 14-3-3 protein was also recently suggested to be involved in ischemic stroke. However, the role of 14-3-3 protein in myocardial infarction (MI)-induced cardiac dysfunction still remains to be determined.
Methods: MI was induced in 12-13 week transgenic mice with cardiac-specific expression of a dominant-negative 14-3-3 protein mutant (DN 14-3-3) by ligating the left anterior descending (LAD) coronary artery. One week later the progression of myocardial dysfunction was monitored by transthoracic echocardiography, 2,3,5-triphenyltetrazolium chloride (TTC) staining, histology to assess hypertrophy, fibrosis and apoptosis, and western blot analyses.
Results: Wild type (WT) and DN 14-3-3 mice subjected to sham surgery display similar cardiac function as indicated by comparable left ventricular (LV) ejection fraction and fractional shortening. However, DN 14-3-3 mice subjected to permanent LAD ligation display reduced survival as compared to WT mice subjected to the same procedure. Interestingly, DN 14-3-3 mice subjected to MI show reduced LV ejection fraction and fractional shortening as well as increased cardiac hypertrophy, fibrosis and apoptosis as compared to their WT counterparts. Mechanistically, DN 14-3-3 mice subjected to MI exhibit increased apoptosis signal regulating kinase (Ask-1), p38 mitogen activated protein kinase phosphorylation and inflammatory cytokines.
Conclusions: Inactivation of the 14-3-3 protein exacerbates cardiac dysfunction and reduces survival in mice subjected to MI, probably via modulation of Ask-1 signaling pathways. These results support the assertion that the enhancement of 14-3-3 protein may provide a novel protective therapy for heart failure.
- © 2011 by American Heart Association, Inc.