A chronic mouse model of myocardial ischemia-reperfusion: essential in cytokine studies.
Reperfusion of the ischemic myocardium is associated with a cytokine cascade that reflects a cellular response to injury. We studied this cascade in the mouse and found that acute surgical trauma in sham-operated animals obscured early changes in cytokine induction that occur during myocardial ischemia-reperfusion (MI/R). Therefore, we utilized a new implantable device that allows occlusion and reperfusion of the left anterior descending coronary artery in a closed-chest mouse at any time after instrumentation. Induction of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha mRNA in the whole heart was examined by RNase protection assay and quantitated by Phosphor- Imager. At 3 h after instrumentation, levels of IL-6 mRNA in sham-operated animals increased above those of control naive hearts, whereas this increase did not occur until after 1 day for TNF-alpha mRNA. The surgical trauma led to exaggeration of I/R cytokine induction with greater variance in response. At 3 days and 1 wk after instrumentation, levels of both IL-6 and TNF-alpha mRNA in sham-operated animals were comparable to those of naive hearts and induction responses in I/R were much less variant. We also found that 1 h of ischemia and 2 h of reperfusion at all time points of recovery (i.e., 3 h and 1, 3, and 7 days after instrumentation) led to a significant increase in IL-6 and TNF-alpha mRNA levels. In addition, 3 h of permanent occlusion, which did not induce any mRNA increase after 1 wk postinstrumentation, caused marked upregulation of IL-6 mRNA in an acutely prepared animal. This study of early cytokine responses evoked by MI/R highlights the need for dissipation of acute surgical trauma by using a chronic, closed-chest mouse preparation.
Nossuli
T O
TO
Section of Cardiovascular Sciences and Cardiology, Department of Medicine, DeBakey Heart Center, Baylor College of Medicine and Methodist Hospital, Houston, Texas 77030, USA.
Lakshminarayanan
V
V
Baumgarten
G
G
Taffet
G E
GE
Ballantyne
C M
CM
Michael
L H
LH
Entman
M L
ML
D000818:Animals; D002908:Chronic Disease; D003331:Coronary Vessels; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D015870:Gene Expression / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000276:immunology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000276:immunology* / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism; D019736:Prostheses and Implants; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha