Abstract
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.
Original language | English |
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Pages (from-to) | 582-92 |
Number of pages | 11 |
Journal | Circulation Research |
Volume | 108 |
Issue number | 5 |
DOIs | |
Publication status | Published - 2011 |
Keywords
- myocardial infarction
- remodeling
- inflammation
- heart failure
- immune system
- MONOCYTE CHEMOATTRACTANT PROTEIN-1
- ATHEROSCLEROTIC LESION DEVELOPMENT
- RENIN-ANGIOTENSIN SYSTEM
- EXTRA DOMAIN-A
- THERAPEUTIC TARGETS
- CARDIAC-FUNCTION
- TRANSGENIC MICE
- FAILURE
- TOLL-LIKE-RECEPTOR-4
- INJURY