Pre-emptive hypoxia-regulated HO-1 gene therapy improves post-ischaemic limb perfusion and tissue regeneration in mice.
Pre-emptive hypoxia-regulated HO-1 gene therapy improves post-ischaemic limb perfusion and tissue regeneration in mice.
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DOI：
10.1093/cvr/cvs284
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发表时间：
2013-01-01
影响因子：
10.8
通讯作者：
Dulak J
中科院分区：
文献类型：
--
作者：
Jazwa A;Stepniewski J;Zamykal M;Jagodzinska J;Meloni M;Emanueli C;Jozkowicz A;Dulak J
血红素加氧酶 - 1（HO - 1）是一种血红素降解酶，可产生一氧化碳、胆红素和铁离子。通过这些化合物，HO - 1发挥抗氧化、抗凋亡和抗炎作用从而减轻细胞损伤。在此，我们研究了HO - 1缺乏以及短暂缺氧/缺血诱导的HO - 1过表达对损伤后后肢恢复的影响。
缺乏功能性HO - 1的小鼠（HO - 1−/−）与野生型同窝小鼠相比，在缺血骨骼肌中修复性新生血管形成减少，血流（BF）恢复受损，并且肌肉细胞死亡增加。用由三个缺氧反应元件（HREs）驱动的携带人HO - 1的质粒载体（pHRE - HO - 1）转染并在0.5%氧气中培养的人微血管内皮细胞（HMEC - 1），其HO - 1表达显著增加。这种上调的HO - 1水平可有效防止过氧化氢诱导的细胞死亡，并促进HMEC - 1细胞的促血管生成表型。更重要的是，当在体内递送时，pHRE - HO - 1显著改善了股动脉结扎小鼠缺血后的足部血流。这些作用与促炎细胞因子（白细胞介素 - 6和趋化因子CXCL1）水平降低以及转移酶介导的dUTP缺口末端标记阳性细胞数量减少有关。此外，递送至小鼠骨骼肌的HO - 1似乎影响肌细胞的再生潜能，因为它显著改变了骨骼肌再生的转录（Pax7、MyoD、肌细胞生成素）和转录后（miR - 146a、miR - 206）调节因子的表达。
我们的结果表明HO - 1在预防严重肢体缺血不良影响方面具有治疗潜力。
Haem oxygenase-1 (HO-1) is a haem-degrading enzyme that generates carbon monoxide, bilirubin, and iron ions. Through these compounds, HO-1 mitigates cellular injury by exerting antioxidant, anti-apoptotic, and anti-inflammatory effects. Here, we examined the influence of HO-1 deficiency and transient hypoxia/ischaemia-induced HO-1 overexpression on post-injury hindlimb recovery. Mice lacking functional HO-1 (HO-1−/−) showed reduced reparative neovascularization in ischaemic skeletal muscles, impaired blood flow (BF) recovery, and increased muscle cell death compared with their wild-type littermates. Human microvascular endothelial cells (HMEC-1) transfected with plasmid vector (pHRE-HO-1) carrying human HO-1 driven by three hypoxia response elements (HREs) and cultured in 0.5% oxygen demonstrated markedly increased expression of HO-1. Such upregulated HO-1 levels were effective in conferring protection against H2O2-induced cell death and in promoting the proangiogenic phenotype of HMEC-1 cells. More importantly, when delivered in vivo, pHRE-HO-1 significantly improved the post-ischaemic foot BF in mice subjected to femoral artery ligation. These effects were associated with reduced levels of pro-inflammatory cytokines (IL-6 and CXCL1) and lower numbers of transferase-mediated dUTP nick-end labelling-positive cells. Moreover, HO-1 delivered into mouse skeletal muscles seems to influence the regenerative potential of myocytes as it significantly changed the expression of transcriptional (Pax7, MyoD, myogenin) and post-transcriptional (miR-146a, miR-206) regulators of skeletal muscle regeneration. Our results suggest the therapeutic potential of HO-1 for prevention of adverse effects in critical limb ischaemia.
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DOI：
10.1073/pnas.0602831103
发表时间：
2006-06-06
影响因子：
11.1
作者：
Rao, Prakash K.;Kumar, Roshan M.;Lodish, Harvey F.
通讯作者：
Lodish, Harvey F.
影响因子：
24
作者：
Pachori, AS;Melo, LG;Dzau, VJ
通讯作者：
Dzau, VJ
影响因子：
4.4
作者：
Soares, MP;Seldon, MP;Bach, FH
通讯作者：
Bach, FH
循环拉伸诱导的 miR-146a 上调通过抑制 Numb 延迟 C2C12 肌原性分化
DOI：
10.1016/j.bbrc.2008.11.041
发表时间：
2009-01-09
影响因子：
3.1
作者：
Kuang, Wei;Tan, Jiali;Liu, Yanpu
通讯作者：
Liu, Yanpu
影响因子：
3.7
作者：
Grochot-Przeczek A;Lach R;Mis J;Skrzypek K;Gozdecka M;Sroczynska P;Dubiel M;Rutkowski A;Kozakowska M;Zagorska A;Walczynski J;Was H;Kotlinowski J;Drukala J;Kurowski K;Kieda C;Herault Y;Dulak J;Jozkowicz A
通讯作者：
Jozkowicz A