Heme oxygenase-1 gene delivery by Sleeping Beauty inhibits vascular stasis in a murine model of sickle cell disease.
Heme oxygenase-1 gene delivery by Sleeping Beauty inhibits vascular stasis in a murine model of sickle cell disease.
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DOI：
10.1007/s00109-010-0613-6
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发表时间：
2010-07
影响因子：
4.7
通讯作者：
Vercellotti, Gregory M.
中科院分区：
文献类型：
--
作者：
Belcher, John D.;Vineyard, Julie V.;Bruzzone, Carol M.;Chen, Chunsheng;Beckman, Joan D.;Nguyen, Julia;Steer, Clifford J.;Vercellotti, Gregory M.
血红素加氧酶-1 (HO-1) 的增加以及血红素降解产物 CO 和胆绿素的施用可抑制镰状细胞病 (SCD) 小鼠模型的血管炎症和血管闭塞。在这项研究中，通过水动力尾静脉注射将带有野生型大鼠 hmox-1 (wt-HO-1) 转座元件的白蛋白 (alb) 启动子驱动的睡美人 (SB) 转座酶质粒递送至 SCD 小鼠。注射八周后，SCD 小鼠的 HO-1 活性和肝脏中的蛋白质表达增加了三到五倍，与氯高铁盐治疗的小鼠相似。免疫组织化学显示肝细胞核周 HO-1 染色增加。通过定量实时聚合酶链式反应限制性片段长度多态性 (qRT-PCR RFLP) 证实了 hmox-1 转基因在肝脏中的信使 RNA 转录，在其他器官中没有检测到转基因表达。所有HO-1过表达小鼠的肝脏均激活核磷酸-p38丝裂原激活蛋白激酶（MAPK）和磷酸-Akt，降低核因子-κB（NF-κB）p65的核表达，并降低血清中可溶性血管细胞粘附分子-1（sVCAM-1）。缺氧诱导的停滞是 SCD 的一个特征，但正常小鼠则不然，尽管皮肤中不存在 hmox-1 转基因表达，这表明 H2O 活性对脉管系统有远端影响，但 wt-HO-1 SCD 小鼠的背侧皮肤皱襞室受到抑制。在注射无义 (ns-) 大鼠 hmox-1 的 SCD 小鼠中，未观察到保护作用，该 hmox-1 编码羧基截短的 HO-1，酶活性很少或没有。我们推测，HO-1基因递送至肝脏对SCD小鼠是有益的，通过降解促氧化血红素、将抗炎血红素降解产物CO和胆绿素/胆红素释放到循环中、激活细胞保护途径并抑制转基因表达远端的血管停滞。
Increases in heme oxygenase-1 (HO-1) and administration of heme degradation products CO and biliverdin inhibit vascular inflammation and vasoocclusion in mouse models of sickle cell disease (SCD). In this study, an albumin (alb) promoter-driven Sleeping Beauty (SB) transposase plasmid with a wild-type rat hmox-1 (wt-HO-1) transposable element was delivered by hydrodynamic tail vein injections to SCD mice. Eight weeks after injection, SCD mice had three- to five-fold increases in HO-1 activity and protein expression in liver, similar to hemin-treated mice. Immunohistochemistry demonstrated increased perinuclear HO-1 staining in hepatocytes. Messenger RNA transcription of the hmox-1 transgene in liver was confirmed by quantitative real-time polymerase chain reaction restriction fragment length polymorphism (qRT-PCR RFLP) with no detectible transgene expression in other organs. The livers of all HO-1 overexpressing mice had activation of nuclear phospho-p38 mitogen-activated protein kinase (MAPK) and phospho-Akt, decreased nuclear expression of nuclear factor-kappa B (NF-κB) p65, and decreased soluble vascular cell adhesion molecule-1 (sVCAM-1) in serum. Hypoxia-induced stasis, a characteristic of SCD, but not normal mice, was inhibited in dorsal skin fold chambers in wt-HO-1 SCD mice despite the absence of hmox-1 transgene expression in the skin suggesting distal effects of HO activity on the vasculature. No protective effects were seen in SCD mice injected with nonsense (ns-) rat hmox-1 that encodes carboxy-truncated HO-1 with little or no enzyme activity. We speculate that HO-1 gene delivery to the liver is beneficial in SCD mice by degrading pro-oxidative heme, releasing anti-inflammatory heme degradation products CO and biliverdin/bilirubin into circulation, activating cytoprotective pathways and inhibiting vascular stasis at sites distal to transgene expression.
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影响因子：
20.3
作者：
Belcher, JD;Bryant, CJ;Vercellotti, GM
通讯作者：
Vercellotti, GM
影响因子：
3.4
作者：
Batzlsperger, Christian A.;Achatz, Stefan;Griese, Daniel P.
通讯作者：
Griese, Daniel P.
影响因子：
15.9
作者：
Kaul, DK;Hebbel, RP
通讯作者：
Hebbel, RP
影响因子：
15.9
作者：
Belcher, JD;Mahaseth, H;Vercellotti, GM
通讯作者：
Vercellotti, GM
影响因子：
2.9
作者：
Huy, NT;Dai, TXT;Kamei, K
通讯作者：
Kamei, K