Vascular heme oxygenase-1 induction suppresses microvascular thrombus formation in vivo
Vascular heme oxygenase-1 induction suppresses microvascular thrombus formation in vivo
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DOI：
10.1161/01.atv.0000118279.74056.8a
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发表时间：
2004-03-01
影响因子：
8.7
通讯作者：
Vollmar, B
中科院分区：
文献类型：
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作者：
Lindenblatt, N;Bordel, R;Vollmar, B
目的：血红素氧合酶-1（HO-1）通过血红素降解提供内源性一氧化碳和胆红素，这两种物质在血管生物学中起着重要作用。目前的研究旨在研究是否诱导HO-1及其副产物调节微血管血栓形成的过程中vivo.Methods和结果-在个别微血管小鼠提睾肌制剂，氯化铁诱导的血栓形成进行了分析，使用活体荧光显微镜。当小鼠腹腔注射血红素，HO-1诱导剂，提睾肌组织的免疫组织化学和蛋白质印迹分析显示显着的诱导HO-1的预处理。在这些动物中，灌注氯化铁溶液诱导小动脉和小静脉血栓形成，然而，显着延迟时，与血栓形成的动物没有HO-1诱导。血晶素处理的小鼠中血栓形成的延迟被HO-1抑制剂锡原卟啉-IX完全钝化，但不被铜原卟啉- IX完全钝化，铜原卟啉- IX不抑制酶。在HO-1阻断的动物中同时给予维生素E类似物Trolox几乎完全恢复了血栓形成的延迟，这意味着除了CO之外，抗氧化剂HO途径代谢物胆红素主要有助于HO-1的抗血栓形成特性。这进一步得到了胆红素在延迟氯化铁诱导的血栓形成方面与氯化血红素一样有效的事实的支持。HO-1诱导的动物显示，在提睾肌组织中P-选择素蛋白表达减少，这最有可能提出延迟血栓growth.Conclusion的分子基础-HO-1活性的局部诱导可能是预防和治疗价值的临床疾病的血栓事件的风险增加。
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 HOpathway 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.