CARD3 Promotes Cerebral Ischemia‐Reperfusion Injury Via Activation of TAK1

Author:

Wu Xiaolin1,Lin Lijin23,Qin Juan‐Juan423,Wang Lifen5,Wang Hao1,Zou Yichun1,Zhu Xueyong423,Hong Ying423,Zhang Yan423,Liu Ye423,Xin Can1,Xu Shuangxiang1,Ye Shengda1,Zhang Jianjian1,Xiong Zhongwei1,Zhu Lihua423,Li Hongliang423,Chen Jincao16,She Zhi‐Gang423ORCID

Affiliation:

1. Department of Neurosurgery Zhongnan Hospital of Wuhan University Wuhan PR China

2. Basic Medical School Wuhan University Wuhan PR China

3. Institute of Model Animals of Wuhan University Wuhan PR China

4. Department of Cardiology Renmin Hospital of Wuhan University Wuhan PR China

5. Operating Theater Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

6. Department of Neurosurgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

Abstract

Background Although multiple signaling cascades and molecules contributing to the pathophysiological process have been studied, the treatments for stroke against present targets have not acquired significant clinical progress. Although CARD3 (caspase activation and recruitment domain 3) protein is an important factor involved in regulating immunity, inflammation, lipid metabolism, and apoptosis, its role in cerebral stroke is currently unknown. Methods and Results Using a mouse model of ischemia‐reperfusion (I‐R) injury based on transient blockage of the middle cerebral artery, we have found that CARD3 expression is upregulated in a time‐dependent manner during I‐R injury. Further animal study revealed that, relative to control mice, CARD3‐knockout mice exhibited decreased inflammatory response and neuronal apoptosis, with reduced infarct volume and lower neuropathological scores. In contrast, neuron‐specific CARD3‐overexpressing transgenic (CARD3‐TG) mice exhibited increased I‐R induced injury compared with controls. Mechanistically, we also found that the activation of TAK1 (transforming growth factor‐β–activated kinase 1) was enhanced in CARD3‐TG mice. Furthermore, the increased inflammation and apoptosis seen in injured CARD3‐TG brains were reversed by intravenous administration of the TAK1 inhibitor 5Z‐7‐oxozeaenol. Conclusions These results indicate that CARD3 promotes I‐R injury via activation of TAK1, which not only reveals a novel regulatory axis of I‐R induced brain injury but also provides a new potential therapeutic approach for I‐R injury.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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