Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice.
MyD88 is an adaptor protein critical for innate immune response against microbial infection and in certain noninfectious tissue injury. The present study examined the role of MyD88 in myocardial inflammation and injury after ischemia-reperfusion (I/R). I/R was produced by coronary artery ligation for 30 min followed by reperfusion. The ratios of area at risk to left ventricle (LV) were similar between wild-type (WT) and MyD88-deficient (MyD88-/-) mice. However, 24 h after I/R, the ratios of myocardial infarction to area at risk were 58% less in MyD88(-/-) than in WT mice (14 +/- 2% vs. 33 +/- 6%, P = 0.01). Serial echocardiographic studies demonstrated that there was no difference in baseline LV contractile function between the two groups. Twenty-four hours after I/R, LV ejection fraction (EF) and fractional shortening (FS) in WT mice were reduced by 44% and 62% (EF, 51 +/- 2%, and FS, 22 +/- 1%, P < 0.001), respectively, and remained depressed on the seventh day after I/R. In comparison, EF and FS in MyD88(-/-) mice were 67 +/- 3% and 33 +/- 2%, respectively, after I/R (P < 0.001 vs. WT). Similarly, LV function, as demonstrated by invasive hemodynamic measurements, was better preserved in MyD88(-/-) compared with WT mice after I/R. Furthermore, when compared with WT mice, MyD88(-/-) mice subjected to I/R had a marked decrease in myocardial inflammation as demonstrated by attenuated neutrophil recruitment and decreased expression of the proinflammatory mediators keratinocyte chemoattractant, monocyte chemoattractant protein-1, and ICAM-1. Taken together, these data suggest that MyD88 modulates myocardial inflammatory injury and contributes to myocardial infarction and LV dysfunction during I/R.
Feng
Yan
Y
Anesthesia Center for Critical Care Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA.
Zhao
Huailong
H
Xu
Xinhua
X
Buys
Emmanuel S
ES
Raher
Michael J
MJ
Bopassa
Jean C
JC
Thibault
Helene
H
Scherrer-Crosbie
Marielle
M
Schmidt
Ulrich
U
Chao
Wei
W
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004452:Echocardiography; D007113:Immunity, Innate / Q000187:drug effects*; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000473:pathology*; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects
D018836:Inflammation Mediators; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D012313:RNA; D009195:Peroxidase