on January 22, 2004
Published online before print January 22, 2004, doi: 10.1161/01.ATV.0000118279.74056.8a
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Submitted on November 14, 2003
Accepted on December 9, 2003
Vascular Heme Oxygenase-1 Induction Suppresses Microvascular Thrombus Formation In Vivo
N. Lindenblatt ;
From the Department of Experimental Surgery (N.L., R.B., B.V.) and the Department of General Surgery (N.L., W.S.), University of Rostock, Rostock, Germany; and the Department of Clinical-Experimental Surgery (M.D.M.), University of Saarland, Homburg/Saar, Germany.
* To whom correspondence should be addressed. E-mail: brigitte.vollmar{at}med.uni-rostock.de.
Objective--By heme degradation, heme oxygenase-1 (HO-1) provides endogenous carbon monoxide and bilirubin, both of which play major roles in vascular biology. The current study aimed to examine whether induction of HO-1 and its byproducts modulate the process of microvascular thrombus formation in vivo.
Methods and Results--In individual microvessels of mouse cremaster muscle preparations, ferric chloride-induced thrombus formation was analyzed using intravital fluorescence microscopy. When mice were pretreated with an intraperitoneal injection of hemin, a HO-1 inducer, immunohistochemistry and Western blot protein analysis of cremaster muscle tissue displayed a marked induction of HO-1. In these animals, superfusion with ferric chloride solution induced arteriolar and venular thrombus formation, which, however, was significantly delayed when compared with thrombus formation in animals without HO-1 induction. The delay in thrombus formation in hemin-treated mice was completely blunted by tin protoporphyrin-IX, a HO-1 inhibitor, but not by copper protoporphyrin-IX, which does not inhibit the enzyme. Coadministration of the vitamin E analogue Trolox in HO-1-blocked animals almost completely restored the delay in thrombus formation, implying that, besides CO, the antioxidant HO pathway metabolite bilirubin mainly contributes to the antithrombotic property of HO-1. This was further supported by the fact that bilirubin was found as effective as hemin in delay of ferric chloride-induced thrombus formation. Animals with HO-1 induction revealed reduced P-selectin protein expression in cremaster muscle tissue, which most probably presented the molecular basis for delayed thrombus growth.
Conclusion--Local induction of HO-1 activity may be of preventive and therapeutic value for clinical disorders with increased risk of thrombotic events.
Key words: thrombosis • platelet • leukocyte • fluorescence microscopy • heme oxygenase • carbon monoxide • bilirubin • P-selectin
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