Endothelial Gata6 deletion reduces monocyte recruitment and proinflammatory macrophage formation and attenuates atherosclerosis through Cmpk2-Nlrp3 pathways
Wenrun Wu,
Wenzhen Bao,
Xiaoli Chen,
Yushi Lu,
Ji Fang,
Jiwen Liu,
Sheng Peng,
Jingjiang Pi,
Brian Tomlinson,
Paul Chan,
Qi Zhang,
Lin Zhang,
Zhongmin Liu,
Jie Liu,
Yuzhen Zhang,
Tao Zhuang
Affiliations
Wenrun Wu
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Wenzhen Bao
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Xiaoli Chen
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Yushi Lu
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Ji Fang
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Jiwen Liu
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Sheng Peng
Department of Trauma, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Jingjiang Pi
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China; Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Brian Tomlinson
Faculty of Medicine, Macau University of Science and Technology, Macau SAR, China
Paul Chan
Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Qi Zhang
Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Lin Zhang
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Zhongmin Liu
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Jie Liu
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China; Corresponding author. Key Laboratory of Arrhythmias of the Ministry of Education of China Research Center for Translational Medicine, Shanghai Heart Failure Research Center Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong New District, Shanghai, 200120, China.
Yuzhen Zhang
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China; Corresponding author. Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong New District, Shanghai, 200120, China.
Tao Zhuang
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Jinshan Hospital, Fudan University, Shanghai, 200032, China; Corresponding author. Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong New District, Shanghai, 200120, China.
Endothelial dysfunction results in chronic vascular inflammation, which is critical for the development of atherosclerotic diseases. Transcription factor Gata6 has been reported to regulate vascular endothelial cell activation and inflammation in vitro. Here, we aimed to explore the roles and mechanisms of endothelial Gata6 in atherogenesis.Endothelial cell (EC) specific Gata6 deletion was generated in the ApoeKO hyperlipidemic atherosclerosis mouse model. Atherosclerotic lesion formation, endothelial inflammatory signaling, and endothelial-macrophage interaction were examined in vivo and in vitro by using cellular and molecular biological approaches. EC-GATA6 deletion mice exhibited a significant decrease in monocyte infiltration and atherosclerotic lesion compared to littermate control mice. Cytosine monophosphate kinase 2 (Cmpk2) was identified as a direct target gene of GATA6 and EC-GATA6 deletion decreased monocyte adherence, migration and pro-inflammatory macrophage foam cell formation through regulation of the CMPK2-Nlrp3 pathway. Endothelial target delivery of Cmpk2-shRNA by intercellular adhesion molecule 2 (Icam-2) promoter-driven AAV9 carrying the shRNA reversed the Gata6 upregulation mediated elevated Cmpk2 expression and further Nlrp3 activation and thus attenuated atherosclerosis. In addition, C–C motif chemokine ligand 5 (Ccl5) was also identified as a direct target gene of Gata6 to regulate monocyte adherence and migration influencing atherogenesis.This study provides direct in vivo evidence of EC-GATA6 involvement in the regulation of Cmpk2-Nlrp3, as well as Ccl5, on monocyte adherence and migration in atherosclerosis development and advances our understanding of the in vivo mechanisms of atherosclerotic lesion development, and meanwhile provides opportunities for future therapeutic interventions.
