Background PDK1 is an essential protein kinase that plays a critical role in mammalian development. Mouse lacking PDK1 leads to multiple abnormalities and embryonic lethality at E9.5. To elucidate the role of PDK1 in the heart, we investigated the cardiac phenotype of mice that lack PDK1 in the heart in different growth periods and the alteration of PDK1 signaling in human failing heart.Methods We employed Cre/loxP system to generate PDK1flox/flox： α-MHC-Cre mice, which specifically deleted PDK1 in cardiac muscle at birth, and tamoxifen-inducible heart-specific PDK1 knockout mice （PDK1flox/flox：MerCreMer mice）, in which PDK1 was deleted in myocardium in response to the treatment with tamoxifen. Transmural myocardial tissues from human failing hearts and normal hearts were sampled from the left ventricular apex to analyze the activity of PDK1/Akt signaling pathways by Western blotting.Results PDK1flox/flox： α-MHC-Cre mice died of heart failure at 5 and 10 weeks old. PDK1flox/flox-MerCreMer mice died of heart failure from 5 to 21 weeks after the initiation of tamoxifen treatment at 8 weeks old. We found that expression levels of PDK1 in human failing heart tissues were significantly decreased compared with control hearts.Conclusion Our results suggest that PDK1 signaling network takes part in regulating cardiac viability and function in mice, and may be also involved in human heart failure disease.
DI Ruo-minFENG Qiu-tingCHANG ZaiLUAN QingZHANG Yang-yangHUANG JunLI Xin-liYANG Zhong-zhou
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.
