Abstract
Disorders of hemostasis lead to vascular pathology. Endothelium-derived gene products play a critical role in the formation and degradation of fibrin. We sought to characterize the importance of these locally produced factors in the formation of fibrin in the cardiac macrovasculature and microvasculature. This study used mice with modifications of the thrombomodulin (TM) gene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-type plasminogen activator (uPA) gene. The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function. The data were fit to a statistical model that may offer a foundation for examination of hemostasis-regulating gene interactions.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cells, Cultured
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Coronary Thrombosis / genetics
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Coronary Thrombosis / metabolism*
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Coronary Thrombosis / pathology
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Disease Models, Animal*
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Endothelium, Vascular / metabolism
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Endothelium, Vascular / pathology
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Fibrin / biosynthesis*
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Fibrosis
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Genetic Predisposition to Disease
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Genotype
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Hemostasis
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Microcirculation
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Myocardium / pathology*
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Thrombomodulin / deficiency
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Thrombomodulin / genetics
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Thrombomodulin / physiology*
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Tissue Plasminogen Activator / deficiency
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Tissue Plasminogen Activator / genetics
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Tissue Plasminogen Activator / physiology*
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Ultrasonography
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Urokinase-Type Plasminogen Activator / deficiency
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Urokinase-Type Plasminogen Activator / genetics
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Urokinase-Type Plasminogen Activator / physiology*
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Ventricular Dysfunction, Left / diagnostic imaging
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Ventricular Dysfunction, Left / genetics
Substances
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Thrombomodulin
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Fibrin
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Tissue Plasminogen Activator
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Urokinase-Type Plasminogen Activator