Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia
Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia
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DOI：
10.1073/pnas.0911921106
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发表时间：
2009-12-01
影响因子：
11.1
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Rey, Sergio;Lee, KangAe;Semenza, Gregg L.
缺血诱导血管生成细胞因子的产生和骨髓源性血管生成细胞（BMDAC）的归巢，但是这些适应性反应由于缺氧诱导因子（HIF）-1 α的表达减少而随着衰老而受损。在这项研究中，我们分析了增加HIF-1 α水平在缺血肢体肌肉注射的AdCA 5，腺病毒编码的组成型活性形式的HIF-1 α，和静脉注射的BMDAC的脯氨酰-4-羟化酶抑制剂二甲基草酰甘氨酸（DMOG）的存在下培养诱导HIF-1表达的影响。联合治疗增加了股动脉结扎老年小鼠的灌注，运动功能和肢体挽救。肌内注射AdCA 5可显著增强BMDAC向缺血肢体的归巢。DMOG处理BMDAC增加了β（2）整联蛋白的细胞表面表达，其介导BMDAC与内皮细胞的粘附增加。DMOG的作用可通过与HIF-1抑制剂地高辛共同给药或与β 2整合素阻断抗体预孵育来消除。用慢病毒LvCA 5转导BMDAC诱导类似于DMOG处理的效果。因此，HIF-1 α基因治疗增加了BMDAC对缺血肌肉的归巢，而BMDAC中的HIF-1诱导增强了它们对血管内皮的粘附，导致联合治疗对组织灌注的协同作用。
Ischemia induces the production of angiogenic cytokines and the homing of bone-marrow-derived angiogenic cells (BMDACs), but these adaptive responses become impaired with aging because of reduced expression of hypoxia-inducible factor (HIF)-1 alpha. In this study, we analyzed the effect of augmenting HIF-1 alpha levels in ischemic limb by intramuscular injection of AdCA5, an adenovirus encoding a constitutively active form of HIF-1 alpha, and intravenous administration of BMDACs that were cultured in the presence of the prolyl-4-hydroxylase inhibitor dimethyloxalylglycine (DMOG) to induce HIF-1 expression. The combined therapy increased perfusion, motor function, and limb salvage in old mice subjected to femoral artery ligation. Homing of BMDACs to the ischemic limb was dramatically enhanced by intramuscular AdCA5 administration. DMOG treatment of BMDACs increased cell surface expression of beta(2) integrins, which mediated increased adherence of BMDACs to endothelial cells. The effect of DMOG was abolished by coadministration of the HIF-1 inhibitor digoxin or by preincubation with a beta(2) integrin-blocking antibody. Transduction of BMDACs with lentivirus LvCA5 induced effects similar to DMOG treatment. Thus, HIF-1 alpha gene therapy increases homing of BMDACs to ischemic muscle, whereas HIF-1 induction in BMDACs enhances their adhesion to vascular endothelium, leading to synergistic effects of combined therapy on tissue perfusion.