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This Article Full Text Full Text (PDF) All Versions of this Article: 287/2/H872    most recent 01083.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Hemdahl, A.-L. Articles by Hansson, G. K. Search for Related Content PubMed PubMed Citation Articles by Hemdahl, A.-L. Articles by Hansson, G. K.

Thrombin inhibitor reduces myocardial infarction in apoE^–/– x LDLR^–/– mice

¹Center for Molecular Medicine, Department of Medicine, and ²Department of Physiology and Pharmacology, Karolinska Institute, SE-171 76, Stockholm, Sweden; and ³Institute of Experimental Clinical Research, Aarhus University Hospital, Skejby Sygehus, DK-8200, Aarhus, Denmark

Submitted 19 December 2003 ; accepted in final form 17 March 2004

We have previously shown that atherosclerotic apolipoprotein E-deficient (apoE^–/–) x LDL receptor-deficient (LDLR^–/–) mice develop myocardial infarction when exposed to hypoxic stress. This study was performed to assess the role of thrombin and thrombosis in this process. ApoE^–/– x LDLR^–/– mice were fed a cholesterol-rich diet for 8 mo and were then subjected to hypoxic stress while receiving isoflurane anesthesia. One group received a bolus dose (5.6 µmol/kg) of the thrombin inhibitor melagatran, and control animals received PBS 10 min before the hypoxic stress. The mice were exposed to 10 min of hypoxia followed by normoxia. Ten minutes after the stress, Alzet pumps delivering melagatran (20 nmol·kg·^–1min^–1) or PBS were implanted, and the mice were allowed to recover for 48 h. The cardiac response was analyzed by histology, immunohistochemistry, and serum troponin T assay. All animals showed reversible ECG changes as a sign of ischemia during hypoxic stress, and 50% developed infarctions afterward as judged by troponin T levels. The group that received thrombin inhibitor had significantly lower troponin T and smaller myocardial infarctions than the PBS-treated group. These data show that thrombin generation is an important pathogenetic factor and suggest that coronary thrombosis is involved in myocardial infarction in atherosclerotic mice. Exposure of atherosclerotic mice to hypoxia leads to myocardial infarction through a two-phase pathway in which acute transient ischemia is followed by thrombin-dependent, irreversible, myocardial ischemia and myocardial cell death.

atherosclerosis; thrombosis; hypoxia; inflammation; apolipoprotein E; low-density lipoprotein receptor

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