doi: 10.1161/01.CIR.0000112575.66565.84
(Circulation. 2004;109:784-789.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Reduced Myocardial Ischemia-Reperfusion Injury in Toll-Like Receptor 4-Deficient Mice
From the Department of Cardiovascular Medicine (J.O., C.B., M.P.); Pulmonary and Critical Care Division (X.L.); Anesthesiology, Perioperative and Pain Medicine (T.B.), Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, Boston; Department of Pathology (L.K.), Harvard Medical School, Boston; and Genzyme Corporation (R.A.K.), Framingham, Mass.
Correspondence to Todd Bourcier, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham & Women’s Hospital, Medical Research Building #502, Boston, MA 02115. E-mail tbourcier{at}rics.bwh.harvard.edu
Received January 14, 2003; de novo received July 14, 2003; revision received October 2, 2003; accepted October 6, 2003.
Background— Myocardial ischemia and reperfusion-induced tissue injury involve a robust inflammatory response, but the proximal events in reperfusion injury remain incompletely defined. Toll-like receptor 4 (TLR4) is a proximal signaling receptor in innate immune responses to lipopolysaccharide of Gram-negative pathogens. TLR4 is also expressed in the heart and vasculature, but a role for TLR4 in the myocardial response to injury separate from microbial pathogens has not been examined. This study assessed the role of TLR4 in myocardial infarction and inflammation in a murine model of ischemia-reperfusion injury.
Methods and Results— Myocardial ischemia-reperfusion (MIR) was performed on 2 strains of TLR4-deficient mice (C57/BL10 ScCr and C3H/HeJ) and controls (C57/BL10 ScSn and C3H/OuJ). Mice were subjected to 1 hour of coronary ligation, followed by 24 hours of reperfusion. TLR4-deficient mice sustained significantly smaller infarctions compared with control mice given similar areas at risk. Fewer neutrophils infiltrated the myocardium of TLR4-deficient Cr mice after MIR, indicated by less myeloperoxidase activity and fewer CD45/GR1-positive cells. The myocardium of TLR4-deficient Cr mice contained fewer lipid peroxides and less complement deposition compared with control mice after MIR. Serum levels of interleukin-12, interferon-
, and endotoxin were not increased after ischemia-reperfusion. Neutrophil trafficking in the peritoneum was similar in all strains after injection of thioglycollate.
Conclusions— TLR4-deficient mice sustain smaller infarctions and exhibit less inflammation after myocardial ischemia-reperfusion injury. The data suggest that in addition to its role in innate immune responses, TLR4 serves a proinflammatory role in murine myocardial ischemia-reperfusion injury.
Key Words: inflammation • myocardial infarction • ischemia
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