A murine model of myocardial microvascular thrombosis.
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.
Christie
P D
PD
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Edelberg
J M
JM
Picard
M H
MH
Foulkes
A S
AS
Mamuya
W
W
Weiler-Guettler
H
H
Rubin
R H
RH
Gilbert
P
P
Rosenberg
R D
RD
D000818:Animals; D002478:Cells, Cultured; D003328:Coronary Thrombosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005337:Fibrin / Q000096:biosynthesis*; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006487:Hemostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008833:Microcirculation; D009206:Myocardium / Q000473:pathology*; D018180:Thrombomodulin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014463:Ultrasonography; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000235:genetics
D018180:Thrombomodulin; D005337:Fibrin; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator