Overexpressing dominant negative MyD88 induces cardiac dysfunction in transgenic mice |
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Authors: | WeiQian Chen ChuanFu Li Xuan Jiang HaiBin Ruan Xin Qi Li Liu QingShun Zhao Xiang Gao |
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Institution: | 1 Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing 210061, China;
2 Department of Surgery, East Tennessee State University, Johnson City, TN 37614, USA;
3 Departments of Gerontology and Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China |
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Abstract: | 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. |
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Keywords: | dilated cardiomyopathy cardiac dysfunction MyD88 Akt GSK-3 |
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