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Am J Physiol Heart Circ Physiol 278: H1049-H1055, 2000;
0363-6135/00 $5.00
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Vol. 278, Issue 4, H1049-H1055, April 2000

A chronic mouse model of myocardial ischemia-reperfusion: essential in cytokine studies

T. O. Nossuli1, V. Lakshminarayanan1, G. Baumgarten2, G. E. Taffet1, C. M. Ballantyne1, L. H. Michael1, and M. L. Entman1

1 Section of Cardiovascular Sciences and Cardiology, Department of Medicine, DeBakey Heart Center, Baylor College of Medicine and Methodist Hospital; and 2 Veterans Administration Medical Center, Winters Center for Heart Failure Research, Houston, Texas 77030

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.

murine; cytokine; interleukin; inflammation; surgery


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