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Published on: May 4, 2015
Thrombin inhibitor reduces myocardial infarction in apoE-/- x LDLR-/- mice
Anne-Louise Hemdahl1, Erling Falk, Peter Thorén
1Department of Medicine, Karolinska Institute, SE-171 76, Stockholm, Sweden.
Insights
Thrombin inhibition significantly reduced myocardial infarction in atherosclerotic mice exposed to hypoxia. This suggests thrombin and coronary thrombosis play key roles in hypoxia-induced heart attacks.
Area of Science:
- Cardiovascular Science
- Thrombosis Research
- Atherosclerosis Models
Background:
- Atherosclerotic mice (apoE(-/-) x LDLR(-/-)) develop myocardial infarction under hypoxic stress.
- The specific roles of thrombin and thrombosis in this process require further investigation.
Purpose of the Study:
- To determine the role of thrombin and thrombosis in myocardial infarction development in atherosclerotic mice subjected to hypoxic stress.
- To assess the efficacy of a thrombin inhibitor in mitigating hypoxia-induced cardiac damage.
Main Methods:
- Atherosclerotic apoE(-/-) x LDLR(-/-) mice were exposed to hypoxic stress.
- Mice received either the thrombin inhibitor melagatran or a placebo (PBS) before and during recovery.
- Cardiac response was evaluated using histology, immunohistochemistry, and serum troponin T levels.
Main Results:
- Hypoxia induced myocardial infarction in 50% of control mice, evidenced by elevated troponin T levels.
- Mice treated with the thrombin inhibitor showed significantly lower troponin T levels.
- Thrombin inhibition resulted in smaller myocardial infarct sizes compared to the placebo group.
Conclusions:
- Thrombin generation is a critical factor in the pathogenesis of myocardial infarction in this mouse model.
- Coronary thrombosis is implicated in the development of myocardial infarction following hypoxic stress in atherosclerotic mice.
- Hypoxia triggers a two-phase pathway leading to myocardial infarction, involving initial ischemia followed by thrombin-dependent irreversible damage.
Abstract:
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 micromol/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 x kg x (-1)min(-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.
