Induction of heme oxygenase-1 is a beneficial response in a murine model of venous thrombosis.
The induction of heme oxygenase-1 (HO-1) may protect against tissue injury. The present study examines the induction of HO-1 in a murine model of venous thrombosis and explores the downstream consequences of this induction. In a model of stasis-induced thrombosis created by ligation of the inferior vena cava, HO-1 expression is markedly induced. Such expression occurs primarily in smooth muscle cells in the venous wall and in leukocytes infiltrating the venous wall and clot. To determine the significance of HO-1 induction in venous thrombosis, this model was imposed in HO-1(+/+) and HO-1(-/-) mice. The initial clot size did not differ in either group by day 2, but was significantly larger in HO-1(-/-) mice by day 10, where an exaggerated inflammatory response in the venous wall was also observed. Following ligation of the inferior vena cava, HO-1(-/-) mice exhibited increased nuclear factor kappaB activation and markedly increased up-regulation of tissue factor, selectins, inflammatory cytokines, and matrix metalloproteinase-9, the latter incriminated in both clot lysis and vascular injury. We conclude that HO-1 deficiency impairs thrombus resolution and exaggerates the inflammatory response to thrombus formation. These findings offer insight into recent observations that polymorphisms in the HO-1 gene may increase the risk for recurrent venous thrombosis and dysfunction of hemodialysis arteriovenous fistulas, the latter caused, in part, by thrombosis.
Tracz
Michal J
MJ
Division of Nephrology and Hypertension, Department of Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Juncos
Julio P
JP
Grande
Joseph P
JP
Croatt
Anthony J
AJ
Ackerman
Allan W
AW
Katusic
Zvonimir S
ZS
Nath
Karl A
KA
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism / Q000473:pathology; D014682:Vena Cava, Inferior / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D020246:Venous Thrombosis / Q000378:metabolism* / Q000473:pathology
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D015850:Interleukin-6; D016328:NF-kappa B; D013925:Thromboplastin; D051547:Heme Oxygenase-1; D020780:Matrix Metalloproteinase 9