Over-expression of a cardiac-specific human dopamine D5 receptor mutation in mice causes a dilated cardiomyopathy through ROS over-generation by NADPH oxidase activation and Nrf2 degradation
| Autor: | Xing Liu, Xiaoliang Jiang, Yunpeng Liu, Yuanyuan Zhang, Zhiwei Yang, Qiang Wei, Yanrong Zhang, Zihao Wang, Yongyan Hu, Wenjie Wang, Pedro A. Jose |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Cardiomyopathy
Dilated 0301 basic medicine Cardiac function curve Genetically modified mouse Dopamine D5 receptor (D5R) NF-E2-Related Factor 2 Clinical Biochemistry Mice Transgenic 030204 cardiovascular system & hematology medicine.disease_cause Biochemistry Nrf2 Cell Line Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Dilated cardiomyopathy (DCM) Receptors Dopamine D5 Receptor lcsh:QH301-705.5 Gene knockout chemistry.chemical_classification Reactive oxygen species Mutation lcsh:R5-920 NADPH oxidase biology Organic Chemistry NADPH Oxidases Reactive oxygen species (ROS) Rats Up-Regulation 3. Good health Cell biology Enzyme Activation Mice Inbred C57BL 030104 developmental biology chemistry lcsh:Biology (General) Dopamine receptor Proteolysis biology.protein cardiovascular system Reactive Oxygen Species lcsh:Medicine (General) Research Paper |
| Zdroj: | Redox Biology, Vol 19, Iss, Pp 134-146 (2018) Redox Biology |
| ISSN: | 2213-2317 |
| Popis: | Dilated cardiomyopathy (DCM) is a severe disorder caused by medications or genetic mutations. D5 dopamine receptor (D5R) gene knockout (D5-/-) mice have cardiac hypertrophy and high blood pressure. To investigate the role and mechanism by which the D5R regulates cardiac function, we generated cardiac-specific human D5R F173L(hD5F173L-TG) and cardiac-specific human D5R wild-type (hD5WT-TG) transgenic mice, and H9c2 cells stably expressing hD5F173L and hD5WT. We found that cardiac-specific hD5F173L-TG mice, relative to hD5WT-TG mice, presented with DCM and increased cardiac expression of cardiac injury markers, NADPH oxidase activity, Nrf2 degradation, and activated ERK1/2/JNK pathway. H9c2-hD5F173L cells also had an increase in NADPH oxidase activity, Nrf2 degradation, and phospho-JNK (p-JNK) expression. A Nrf2 inhibitor also increased p-JNK expression in H9c2-hD5F173L cells but not in H9c2-hD5WT cells. We suggest that the D5R may play an important role in the preservation of normal heart function by inhibiting the production of reactive oxygen species, via inhibition of NADPH oxidase, Nrf2 degradation, and ERK1/2/JNK pathways. Keywords: Dilated cardiomyopathy (DCM), Dopamine D5 receptor (D5R), Reactive oxygen species (ROS), Nrf2 |
| Databáze: | OpenAIRE |
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