McAllister Shane C, Hansen Scott G, Ruhl Rebecca A, Raggo Camilo M, DeFilippis Victor R, Greenspan Deborah, Früh Klaus, Moses Ashlee V
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, USA.
Blood. 2004 May 1;103(9):3465-73. doi: 10.1182/blood-2003-08-2781. Epub 2004 Jan 15.
Kaposi sarcoma (KS) is the most common AIDS-associated malignancy and is characterized by angiogenesis and the presence of spindle cells. Kaposi sarcoma-associated herpesvirus (KSHV) is consistently associated with all clinical forms of KS, and in vitro infection of dermal microvascular endothelial cells (DMVECs) with KSHV recapitulates many of the features of KS, including transformation, spindle cell proliferation, and angiogenesis. To study the molecular mechanisms of KSHV pathogenesis, we compared the protein expression profiles of KSHV-infected and uninfected DMVECs. This comparison revealed that heme oxygenase-1 (HO-1), the inducible enzyme responsible for the rate-limiting step in heme catabolism, was up-regulated in infected endothelial cells. Recent evidence suggests that the products of heme catabolism have important roles in endothelial cell biology, including apoptosis and angiogenesis. Here we show that HO-1 mRNA and protein are up-regulated in KSHV-infected cultures. Comparison of oral and cutaneous AIDS-KS tissues with normal tissues revealed that HO-1 mRNA and protein were also up-regulated in vivo. Increased HO-1 enzymatic activity in vitro enhanced proliferation of KSHV-infected DMVECs in the presence of free heme. Treatment with the HO-1 inhibitor chromium mesoporphyrin IX abolished heme-induced proliferation. These data suggest that HO-1 is a potential therapeutic target for KS that warrants further study.
卡波西肉瘤（KS）是最常见的与艾滋病相关的恶性肿瘤，其特征为血管生成和梭形细胞的存在。卡波西肉瘤相关疱疹病毒（KSHV）始终与KS的所有临床形式相关，用KSHV体外感染真皮微血管内皮细胞（DMVECs）可重现KS的许多特征，包括转化、梭形细胞增殖和血管生成。为了研究KSHV发病机制的分子机制，我们比较了KSHV感染和未感染的DMVECs的蛋白质表达谱。这种比较显示，血红素加氧酶-1（HO-1），即负责血红素分解代谢限速步骤的诱导酶，在感染的内皮细胞中上调。最近的证据表明，血红素分解代谢产物在内皮细胞生物学中具有重要作用，包括细胞凋亡和血管生成。在这里我们表明，HO-1 mRNA和蛋白质在KSHV感染的培养物中上调。将口腔和皮肤艾滋病相关KS组织与正常组织进行比较发现，HO-1 mRNA和蛋白质在体内也上调。体外HO-1酶活性增加在游离血红素存在的情况下增强了KSHV感染的DMVECs的增殖。用HO-1抑制剂中卟啉铬IX处理可消除血红素诱导的增殖。这些数据表明，HO-1是KS的一个潜在治疗靶点，值得进一步研究。
