Myeloid differentiation protein-88(MyD88) is a crucial adaptor protein in the innate immune response.A protective role for MyD88 in normal cardiac function has been proposed in a surgical hypertrophic model.To assess the in vivo role of MyD88 in cardiac remodeling,we generated transgenic mice with cardiac-restricted expression of a dominant negative mutant of MyD88(dnMyD88).Surprisingly,dnMyD88 transgenic mice displayed characteristic features of heart failure;including heart weight increase,cardiomyocytes enlargement,interstitial fibrosis,and re-expression of "fetal" genes.Echocardiographic examination of dnMyD88 hearts revealed dilated chamber volume and reduced cardiac contractility.DnMyD88 mice died from heart failure before they were 7 months old,as shown by Kaplan-Meier analysis.Additionally,the heart failure phenotype of dnMyD88 mice was associated with abnormal activation of the Akt/GSK-3β signaling pathway.These data provide the first evidence that normal MyD88 signaling is crucial for maintaining the physiological function of the adult heart.
