Thrombin inhibitor reduces myocardial infarction in apoE<sup>−/−</sup>× LDLR<sup>−/−</sup>mice

Hemdahl, Anne-Louise; Falk, Erling; Thorén, Peter; Hansson, Göran K.

doi:10.1152/ajpheart.01083.2003

Cited by 13 publications

(14 citation statements)

References 34 publications

(40 reference statements)

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“…Marked reduction in plaque size was reported when mice were treated with the thrombin inhibitor dabigatran (181). Similar results were reported with another thrombin inhibitor, melagatran (117,746). Several other genes that affect clotting or platelet activity are also reviewed in TABLE 10.…”

Section: B Thrombosis and Atherosclerosissupporting

confidence: 64%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Section: B Thrombosis and Atherosclerosissupporting

confidence: 64%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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“…Hemdahl et al reported protective effects of sc melagatran in a mouse model of hypoxic stress induced myocardial infarction. 24 In the present study, we show for the first time that oral administration of melagatran attenuated the progression of ath- erosclerotic plaques in brachiocephalic arteries of apoEϪ/Ϫ mice. Melagatran had beneficial effects on both size and composition of the advanced atherosclerotic lesions.…”

Section: Discussionsupporting

confidence: 53%

Melagatran Reduces Advanced Atherosclerotic Lesion Size and May Promote Plaque Stability in Apolipoprotein E– Deficient Mice

Bea

Kreuzer

Preusch

et al. 2006

ATVB

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Objective-Inflammatory mechanisms are involved in atherosclerotic plaque rupture and subsequent thrombin formation.Thrombin not only plays a central role in thrombus formation and platelet activation, but also in the induction of inflammatory processes. We assessed the hypothesis that melagatran, a direct thrombin inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions. Methods and Results-Melagatran (500 mol/kg/d) or control diet was administered to apolipoprotein E-deficient mice (nϭ54) with advanced atherosclerotic lesions. A cute coronary syndromes are related to the formation and disruption of atherosclerotic plaques. Advanced atherosclerotic lesions are characterized by the presence of a lipid rich necrotic core, which is separated from the vessel lumen by a protective fibrous cap. Most acute coronary events result from the rupture of this fragile fibrous cap. As the cap ruptures, the cells and soluble factors of the coagulant system are exposed to this large pool of procoagulant components, resulting in platelet activation and aggregation, thrombin generation, and the development of a large, often occlusive, thrombus. 1,2 There is increasing evidence that thrombin also participates in atherosclerotic heart disease in ways that do not directly involve thrombus formation; it acts as a signaling molecule, through protease-activated receptors. 3 These signaling events concern virtually all aspects of vascular biology, including vessel tone, 4 cell differentiation, 5 migration, 6 proliferation, 7,8 angiogenesis, 9 and vascular pathology such as atherosclerosis and inflammation. 10 -12 In the present study, we tested the hypothesis, whether administration of the direct thrombin inhibitor melagatran prevents initiation of atherosclerosis in C57BL/6J mice and/or alters size and composition of advanced atherosclerotic lesions in hyperlipidemic apolipoprotein E-deficient mice. Methods Animals and Drug TreatmentThirty-week-old female apolipoprotein E-deficient mice (Charles River WIGA, Salzfeld, Germany) 13 (strain name B6.129P2) on a C57BL/6J background (nϭ54) were kept within the animal care facility of the University of Heidelberg. 28 mice were fed a chow diet supplemented with melagatran (500 mol/kg/d) for 22 weeks, 26 mice received regular chow diet. Ximelagatran, which is rapidly bioconverted into its active form, melagatran is generally used in Original

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“…We have previously demonstrated that stress can induce MI in atherosclerotic mice (Caligiuri et al 1999, Hemdahl et al 2004). Our present data show that the stress challenge triggers a process with cardiac instability which leads to irreversible ischaemia and MI.…”

Section: Discussionmentioning

confidence: 99%

“…While the initiation and early stages of progression of atherosclerosis have been widely investigated, the complications leading to myocardial infarction (MI) have remained obscure, partly due to lack of suitable models. When such mice develop advanced coronary atherosclerosis, these stimuli initiate an irreversible endothelin-dependent vasospasm which is later followed by thrombin activation causing coronary thrombosis, irreversible ischaemia and MI (Hemdahl et al 2004). When such mice develop advanced coronary atherosclerosis, these stimuli initiate an irreversible endothelin-dependent vasospasm which is later followed by thrombin activation causing coronary thrombosis, irreversible ischaemia and MI (Hemdahl et al 2004).…”

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confidence: 99%