BAY 11-7082, a nuclear factor-κB inhibitor, reduces inflammation and apoptosis in a rat cardiac ischemia-reperfusion injury model.
Despite development of therapeutic modalities, myocardial ischemia-reperfusion (I/R) injury remains an important cause of cardiac dysfunction. Multiple strategies exist experimentally, but few are clinically available. Nuclear factor kappa-B (NF-κB) is a key transcription factor in the inflammatory response and is implicated in I/R injury. We hypothesized that the NFκB inhibitor BAY 11-7082 (BAY) would decrease the extent of injury after myocardial I/R. Hypoxia-reoxygenation (H/R) was induced in rat neonatal cardiomyocytes with or without BAY pretreatment. NF-κB activation, vascular cell adhesion molecule (VCAM)-1, and monocyte chemoattractant protein (MCP)-1 were assayed by immunocytochemistry, Western blot or reverse transcriptase-polymerase chain reaction (RT-PCR). Sprague-Dawley rats (n = 7) were administered BAY (130 µg/kg) and I/R was induced by ligation of the left anterior descending artery (LAD) for 30 minutes followed by reperfusion. Infarct size was analyzed after 24 hours. At 2 weeks, echocardiography was performed to evaluate ventricular function and hearts were analyzed for fibrosis and apoptosis. BAY treatment inhibited NF-κB p65 activation, as well as VCAM-1 and MCP-1 expression induced by H/R in cardiomyocytes. Compared with control rats, BAY pretreated rats showed reduced infarct size. Echocardiograms demonstrated preserved systolic function as a fractional shortening in the BAY+I/R group (P < 0.05). Fibrosis was reduced in the BAY+I/R group (P < 0.05) and apoptosis was also reduced in the BAY+I/R group (P < 0.05).In the rat myocardial I/R injury model, BAY significantly reduced the infarct size, and preserved myocardial function. These data demonstrate that a currently available and well-tolerated inhibitor of NF-κB can decrease the risk of myocardial injury associated with I/R.
Heart Research Center, Chonnam National University Hospital, Gwangju, South Korea.
Yong Sook
YS
Kim
Ji Su
JS
Kim
Jin Sook
JS
Kwon
Myung Ho
MH
Jeong
Jeong Gwan
JG
Cho
Jong Chun
JC
Park
Jung Chaee
JC
Kang
Youngkeun
Y
Ahn
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007249:Inflammation / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D018932:Chemokine CCL2; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones