CARD3 Promotes Cerebral Ischemia-Reperfusion Injury Via Activation of TAK1.

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.

• Authors: Xiaolin Wu, Lijin Lin, Juan-Juan Qin, Lifen Wang, Hao Wang, Yichun Zou, Xueyong Zhu, Ying Hong, Yan Zhang, Ye Liu, Can Xin, Shuangxiang Xu, Shengda Ye, Jianjian Zhang, Zhongwei Xiong, Lihua Zhu, Hongliang Li, Jincao Chen, Zhi-Gang She
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 9 Issue 9 Pg. e014920 (05 05 2020) ISSN: 2047-9980 [Electronic] England
• PMID: 32349637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Receptor-Interacting Protein Serine-Threonine Kinase 2
• Ripk2 protein, mouse
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Animals
• Apoptosis
• Brain (enzymology, pathology)
• Cells, Cultured
• Disease Models, Animal
• Enzyme Activation
• Infarction, Middle Cerebral Artery (enzymology, genetics, pathology)
• Inflammation Mediators (metabolism)
• MAP Kinase Kinase Kinases (metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Neurons (enzymology, pathology)
• Phosphorylation
• Rats, Sprague-Dawley
• Receptor-Interacting Protein Serine-Threonine Kinase 2 (deficiency, genetics, metabolism)
• Reperfusion Injury (enzymology, genetics, pathology)
• Signal Transduction