Pre-emptive hypoxia-regulated HO-1 gene therapy improves post-ischaemic limb perfusion and tissue regeneration in mice

被引：43

作者：

Jazwa, Agnieszka ^{[1
]}

Stepniewski, Jacek ^{[1
]}

Zamykal, Martin ^{[1
]}

Jagodzinska, Jolanta ^{[1
]}

Meloni, Marco ^{[2
]}

Emanueli, Costanza ^{[2
]}

Jozkowicz, Alicja ^{[1
]}

Dulak, Jozef ^{[1
]}

机构：

[1] Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Med Biotechnol, PL-30387 Krakow, Poland

[2] Univ Bristol, Sch Clin Sci, Regenerat Med Sect, Lab Vasc Pathol & Regenerat, Bristol, Avon, England

来源：

CARDIOVASCULAR RESEARCH | 2013年 / 97卷 / 01期

基金：

英国惠康基金;

关键词：

Angiogenesis; Gene therapy; HO-1; MicroRNA; Satellite cells; HEME OXYGENASE-1 GENE; EXPRESSION; ISCHEMIA; INHIBITION; DIFFERENTIATION; PROTOPORPHYRIN; ANGIOGENESIS; MECHANISMS; INDUCTION; INJURY;

D O I：

10.1093/cvr/cvs284

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：115 / 124

页数：10

共 36 条

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