期刊
CIRCULATION RESEARCH
卷 108, 期 5, 页码 582-U110出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.110.224428
关键词
myocardial infarction; remodeling; inflammation; heart failure; immune system
资金
- Netherlands Organisation for Scientific Research (NWO)
- Utrecht University [017.004.004]
- Netherlands Heart Foundation [2010.T001]
- Bekales Foundation
- US Department of Veterans Affairs
- See Foundation
Rationale: The extracellular matrix may induce detrimental inflammatory responses on degradation, causing adverse cardiac remodeling and heart failure. The extracellular matrix protein fibronectin-EDA (EIIIA; EDA) is upregulated after tissue injury and may act as a danger signal for leukocytes to cause adverse cardiac remodeling after infarction. Objective: In the present study, we evaluated the role of EDA in regulation of postinfarct inflammation and repair after myocardial infarction. Methods and Results: Wild-type and EDA(-/-) mice underwent permanent ligation of the left anterior coronary artery. Despite equal infarct size between groups (38.2+/-4.6% versus 38.2+/-2.9% of left ventricle; P=0.985), EDA(-/-) mice exhibited less left ventricular dilatation and enhanced systolic performance compared with wild-type mice as assessed by serial cardiac MRI measurements. In addition, EDA(-/-) mice exhibited reduced fibrosis of the remote area without affecting collagen production, cross-linking, and deposition in the infarct area. Subsequently, ventricular contractility and relaxation was preserved in EDA(-/-). At tissue level, EDA(-/-) mice showed reduced inflammation, metalloproteinase 2 and 9 activity, and myofibroblast transdifferentiation. Bone marrow transplantation experiments revealed that myocardium-induced EDA and not EDA from circulating cells regulates postinfarct remodeling. Finally, the absence of EDA reduced monocyte recruitment as well as monocytic Toll-like receptor 2 and CD49d expression after infarction. Conclusions: Our study demonstrated that parenchymal fn-EDA plays a critical role in adverse cardiac remodeling after infarction. Absence of fn-EDA enhances survival and cardiac performance by modulating matrix turnover and inflammation via leukocytes and fibroblasts after infarction. (Circ Res. 2011; 108: 582-592.)
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