Induction of Heme Oxygenase-1 is a Beneficial Response in a Murine Model of Venous Thrombosis

Abstract

؊/؊ mice exhibited increased nuclear factor B 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.

Increased risk of venous thromboembolism is associated with genetic variation in heme oxygenase-1 in Blacks

“…Additionally, the products of the degradation of heme, ionic iron, CO and biliverdin, or their immediate downstream products also contribute to an anti-oxidative, anti-inflammatory state and have anti-thrombotic activity [12,24,25]. DNA polymorphisms which impair or reduce HO-1 response may therefore lead to increased risk of endothelial dysfunction and vascular disease, including resolution of venous thrombosis [14]. Human patients with shorter HMOX1 promoter (GT) n repeat alleles might benefit by having a stronger inducible heme oxygenase response [15,26], and indeed, long alleles were associated with increased risk of recurrent VTE in the only other study to date to examine the role of this polymorphism in VTE [16].…”

“…Knockout mice which do not express HO-1 have been shown to have an enhanced inflammatory response and significantly impaired resolution of experimentally induced venous thrombosis [14]. Humans carry a (GT) n microsatellite (rs3074372) located in the promoter of the heme oxygenase-1 (HMOX1) gene that may influence the level of HO-1 response whereby individuals with lower numbers of repeats have higher inducible expression [15].…”

Characterization of a Model of an Arteriovenous Fistula in the Rat

“…[23][24][25] The nuclear extract (5 g) from five femoral veins of shamoperated rats or three venous limbs of AVFs were pooled for each binding reaction. A double-stranded consensus oligonucleotide for nuclear factor (NF)-B or activator protein (AP)-1 (catalog nos.…”

“…The resulting cDNA was used in quantitative real-time PCR analysis as in our earlier studies. [23][24][25] Reactions were performed on an ABI Prism 7900HT (Applied Biosystems, Foster City, CA) using TaqMan Mastermix reagents (part no. 4309169, Applied Biosystems).…”

“…[23][24][25] Briefly, proteins (25 to 60 g) were separated on 10% Tris-HCl gels (BioRad) and transferred to polyvinylidene fluoride membranes. Primary antibodies for phosphorylated (p)-endothelial (e)NOS, eNOS, inducible (i)NOS (catalog nos.…”