Bruton tyrosine kinase promotes wound healing after myocardial infarction by inhibiting the transcription of u-PA.

Autor:	Dong Z; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China; Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China., Zhu JB; Department of Cardiology, The First Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang, China' and 'Jiangxi Hypertension Research Institute, Nanchang, China., Cheng S; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China., Weng XY; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China., Sun XL; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China., Qian JY; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China., Zou YZ; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China., Sun AJ; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China. Electronic address: sun.aijun@zs-hospital.sh.cn., Wang SJ; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China; Minhang Hospital, Fudan University, Shanghai, China. Electronic address: wang.shijun@zs-hospital.sh.cn., Ma LL; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China. Electronic address: mllsdjn@126.com., Ge JB; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China.
Jazyk:	angličtina
Zdroj:	Free radical biology & medicine [Free Radic Biol Med] 2024 Dec 04; Vol. 227, pp. 260-275. Date of Electronic Publication: 2024 Dec 04.
DOI:	10.1016/j.freeradbiomed.2024.12.008
Abstrakt:	Backgrounds: Bruton tyrosine kinase (BTK), which is highly expressed in immune cells, plays a critical role in regulating the function of macrophages. A growing body of evidence has demonstrated that the accumulation of macrophages in cardiac tissue after myocardial infarction (MI) significantly affects wound healing and ventricular remodeling during the early phase of repair after MI. However, the role of BTK in cardiac repair post-MI, especially in macrophage-mediated repair, remains unclear. Methods: MI was induced by permanent left anterior descending (LAD) artery ligation in wild-type (WT) mice and macrophage-specific BTK-knockout (BTK MAC-KO ) mice. Expression of BTK and phosphorylated BTK were assessed by western blotting. Then, RNA sequencing and ChIP-qPCR assay were performed to explore potential BTK targets and transcriptional regulatory sites. Results: BTK, which was mainly expressed in macrophages, was upregulated in mice after MI. Compared with WT mice, BTK MAC-KO mice had significantly greater mortality due to heart rupture, reduced wall thickness and severe impairment of left ventricular (LV) function after MI. In addition, increased matrix metalloproteinase-9 (MMP-9) expression and decreased α-SMA and collagen expression were observed in BTK MAC-KO mice after MI. Further experiments revealed that BTK deficiency in macrophages reduces the expression of VEGF and impairs angiogenesis after MI. By RNA sequencing, we found that Nf-kB family genes, as well as the urokinase-type plasminogen activator (uPA), were significantly upregulated in BTK-deficient macrophages. By ChIP-qPCR analysis, we confirmed that uPA was transcriptionally activated by the Nf-kB p65 subunit. Finally, the application of plasminogen activator inhibitor-1 (PAI-1), an uPA inhibitor, markedly protected against cardiac rupture, lowered the mortality rate, and improved cardiac function by increasing collagen deposition and promoting tissue healing in BTK MAC-KO mice after MI. Conclusions: The present study identifies PAI-1 as a novel cardioprotective agent for cardiac repair post-MI that increases collagen deposition and promotes tissue healing. A therapeutic strategy targeting BTK may be a promising treatment for cardiac repair post-MI. Competing Interests: Declaration of competing interest All the authors declare that they have no conflict of interest. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Full Text from ScienceDirect