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

Redox Biology
Xiaoliang JiangZhiwei Yang

Abstract

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.

Citations

Apr 9, 2019·Journal of the American Heart Association·Shaoxiong WangChunyu Zeng
Jul 3, 2020·Frontiers in Bioengineering and Biotechnology·Xumin LiTim Forouzanfar
Dec 19, 2020·Chronic Diseases and Translational Medicine·Tian-Rui Hua, Shu-Yang Zhang
Nov 18, 2021·Journal of Cellular and Molecular Medicine·Xumin LiGang Wu

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Methods Mentioned

BETA
transgenic
transfection
PCR
immunoprecipitation
co-immunoprecipitation
ubiquitination
nuclear translocation

Software Mentioned

SPSS

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