(Circulation. 2001;103:2296.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Ischemia-Reperfusion of Rat Myocardium Activates Nuclear Factor-
B and Induces Neutrophil Infiltration Via Lipopolysaccharide-Induced CXC Chemokine
From the Department of Medicine, University of Texas Health Science Center at San Antonio, South Texas Veterans Healthcare System, Audie Murphy Division, San Antonio, Tex (B.C., G.L.F.), and the Department of Pediatrics, UCLA School of Medicine, Los Angeles, Calif (J.B.S.).
Correspondence to Bysani Chandrasekar, DVM, PhD, Medicine/Cardiology, The University of Texas Health Science Center, 7703 Floyd Curl Dr, San Antonio, TX 78229-3900. E-mail chandraseka{at}uthscsa.edu
Background—Mechanisms by which neutrophils are attracted to the myocardium in ischemia/reperfusion are not fully defined. Lipopolysaccharide-induced CXC chemokine (LIX), cytokine-induced neutrophil chemoattractant (KC), and macrophage inflammatory protein-2 (MIP-2) are rodent chemokines with potent neutrophil-chemotactic activity. The goals of the present study were to evaluate the roles of these chemokines in a rat model of ischemia/reperfusion and to examine the mechanisms of chemokine induction by oxidative stress and cytokines in cultured cardiomyocytes.
Methods and
Results—Male Wistar-Kyoto rats underwent 45
minutes of ligation of the left anterior descending coronary
artery, followed by reperfusion for various periods. Compared with
sham-operated controls, myocardium from reperfused animals
had higher levels of free radicals, increased neutrophil infiltration
evidenced histologically and by elevated
myeloperoxidase activity, and increased nuclear factor (NF)-
B DNA
binding activity. Ischemia-reperfusion also induced the
expression of interleukin-1ß, tumor necrosis factor (TNF)-
, LIX,
KC, and MIP-2 mRNA and protein. LIX expression was localized to
resident myocardial cells, whereas KC and MIP-2 were expressed only in
infiltrating inflammatory cells. Neutralization of LIX inhibited 79%
of neutrophil infiltration into previously ischemic
myocardium. In contrast, neutralization of KC and MIP-2
reduced neutrophil infiltration by only 28% and 37%, respectively. In
cultured cardiomyocytes, LIX expression was induced by
oxidative stress or TNF- and was blocked by the NF-B
inhibitor
pyrrolidinedithiocarbamate.
Conclusions—LIX is
expressed by resident myocardial cells during
ischemia-reperfusion and is induced in cultured
cardiomyocytes by oxidative stress or TNF- via NF-B
activation. Although KC and MIP-2 are expressed by inflammatory cells
infiltrating the myocardium during reperfusion after
ischemia, neutrophil recruitment to reperfused rat
myocardium is mainly due to cardiomyocyte
expression of LIX.
Key Words: ischemia • reperfusion • chemokines • inflammation
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