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Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX 77030
Infarct healing is dependent on an inflammatory reaction that results in leukocyte infiltration and clearance of the wound from dead cells and matrix debris. However, optimal infarct healing requires timely activation of "stop signals" that suppress inflammatory mediator synthesis and mediate resolution of the inflammatory infiltrate, promoting formation of a scar. A growing body of evidence suggests that interactions involving the transmembrane receptor CD44 may play an important role in resolution of inflammation and migration of fibroblasts in injured tissues. We examined the role of CD44 signaling in infarct healing and cardiac remodeling using a mouse model of reperfused infarction. CD44 expression was markedly induced in the infarcted myocardium and was localized on infiltrating leukocytes, wound myofibroblasts, and vascular cells. In comparison with wild-type mice, CD44–/– animals showed enhanced and prolonged neutrophil and macrophage infiltration and increased expression of proinflammatory cytokines following myocardial infarction. In CD44null infarcts, the enhanced inflammatory phase was followed by decreased fibroblast infiltration, reduced collagen deposition, and diminished proliferative activity. Isolated CD44null cardiac fibroblasts had reduced proliferation upon stimulation with serum and decreased collagen synthesis in response to TGF-β in comparison to wild-type fibroblasts. The healing defects in CD44–/– mice were associated with enhanced dilative remodeling of the infarcted ventricle, without affecting the size of the infarct. Our findings suggest that CD44-mediated interactions are critically involved in infarct healing. CD44 signaling is important for resolution of the postinfarction inflammatory reaction and regulates fibroblast function.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health R01 HL-76246, R01 HL-85440, and the American Heart Association.
2 Address correspondence and reprint requests to Dr. Nikolaos G. Frangogiannis, Section of Cardiovascular Sciences, Baylor College of Medicine, One Baylor Plaza BCM620, Houston, TX 77030. E-mail address: ngf{at}bcm.tmc.edu
3 Abbreviations used in this paper: WT, wild type; KO, knockout; qPCR, quantitative PCR; RPS3, ribosomal protein S3; 
-SMA, -smooth muscle actin; PCNA, proliferating cell nuclear Ag; HA, hyaluronic acid; LVEDV, left ventricular end-diastolic volume; RPA, RNA protection assay; IP, IFN-
-inducible protein; RPA, ribonuclease protection assay; pNS, p not significant.
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