Suppression of NF-κB reduces myocardial no-reflow.
No-reflow phenomenon is a risk factor which severely compromises the benefits of coronary revascularization in patients with acute myocardial infarction. Inflammatory response, as an essential component of cardiac ischemia/reperfusion (I/R) injury, has been suggested to contribute to the myocardial no-reflow. Since nuclear factor kappa B (NF-κB) is a key mediator of inflammation, we reasoned that inhibition of NF-κB might reduce the extent of no-reflow. To test this hypothesis, the left circumflex coronary arteries of New Zealand white male rabbits were ligated for 1.5 h, followed by reperfusion for 1 h to induce I/R injury. Pretreatment of the rabbits with a specific NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), significantly attenuated neutrophil infiltration in the no-reflow area as well as the expansion of no-reflow. These beneficial effects were associated with a marked reduction in the serum levels of myocardial induced I/R tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and CXCL16. Consistently, simulative I/R culture of human umbilical vein endothelial cells (HUVECs) resulted in an increase of TNF-α, ICAM-1 and CXCL16, and all of these changes were significantly suppressed by pretreatment of the cells with PDTC or with siRNA-mediated p65 knockdown. Our data thus suggest that inhibition of NF-κB may reduce I/R-associated myocardial no-reflow through reduction of myocardial inflammation.
Department of Cardiology, Beijing Anzhen Hospital, the Capital Medical University, China.
Min
M
Zeng
Hongbing
H
Yan
Yi
Y
Chen
Han-Jun
HJ
Zhao
Yuan
Y
Lv
Cheng
C
Liu
Peng
P
Zhou
Bo
B
Zhao
D000818:Animals; D002460:Cell Line; D019743:Chemokines, CXC / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019743:Chemokines, CXC; D016328:NF-kappa B; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C066229:prolinedithiocarbamate; D011392:Proline