Of Mice and Dogs

Abstract

Large animal models have provided much of the descriptive data regarding the cellular and molecular events in myocardial infarction and repair. The availability of genetically altered mice may provide a valuable tool for specific cellular and molecular dissection of these processes. In this report we compare closed chest models of canine and mouse infarction/reperfusion qualitatively and quantitatively for temporal, cellular, and spatial differences. Much like the canine model, reperfused mouse hearts are associated with marked induction of endothelial adhesion molecules, cytokines, and chemokines. Reperfused mouse infarcts show accelerated replacement of cardiomyocytes by granulation tissue leading to a thin mature scar at 14 days, when the canine infarction is still cellular and evolving. Infarcted mouse hearts demonstrate a robust but transient postreperfusion inflammatory reaction, associated with a rapid up-regulation of interleukin-10 and transforming growth factor-␤. Unlike canine infarcts, infarcted mouse hearts show only transient macrophage infiltration and no significant mast cell accumulation. In correlation, the growth factor for macrophages, M-CSF, shows modest and transient up-regulation in the early days of reperfusion; and the obligate growth factor for mast cells, stem cell factor, SCF, is not induced. In summary, the postinfarction inflammatory response and resultant repair in the mouse heart shares many common characteristics with large mammalian species, but has distinct temporal and qualitative features. These important species-specific differences should be considered when interpreting findings derived from studies using genetically altered mice. For almost a century, experimental models of myocardial infarction have contributed to our understanding of the pathobiology of myocardial infarction. Large animal models have been extensively used to study the mechanisms involved in myocardial injury and repair 1,2 and have significantly contributed to our understanding of the pathological process of myocardial infarction. However, large animal studies have significant limitations in investigating the functional role of specific genes in myocardial ischemia. Recent advances in transgenic and gene targeting approaches have allowed sophisticated manipulations of genes whose functions may be important in injury and repair following myocardial infarction.3 Because of technical and economic considerations, these experiments are largely confined to the mouse. 4,5 To capitalize on these advances in gene targeting technology murine models of experimental myocardial infarction have been developed 6,7 and have been extensively used to dissect the mechanisms involved in ischemic myocardial injury. 8 -10 However, extrapolation of the findings derived from murine experiments to the human pathobiology requires similar disease mechanisms in both species. Despite the widespread use of murine models of myocardial infarction, detailed studies of the cellular and molecular events associated with repair of the mous...

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