Ang-1 gene therapy inhibits hypoxia-inducible factor-1alpha (HIF-1alpha)-prolyl-4-hydroxylase-2, stabilizes HIF-1alpha expression, and normalizes immature vasculature in db/db mice.
Ang-1 gene therapy inhibits hypoxia-inducible factor-1alpha (HIF-1alpha)-prolyl-4-hydroxylase-2, stabilizes HIF-1alpha expression, and normalizes immature vasculature in db/db mice.
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ANG-1基因治疗抑制缺氧诱导因子-1alpha（HIF-1Alpha） - 丙基-4-羟化酶2，稳定HIF-1Alpha的表达，并使DB/DB小鼠中未成熟的脉管系统归一化。
DOI：
10.2337/db08-0503
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发表时间：
2008-12
期刊：
影响因子：
7.7
通讯作者：
Stinnett, Amanda
中科院分区：
文献类型：
--
作者：
Chen, Jian-Xiong;Stinnett, Amanda
目的-糖尿病血管生成受损与缺氧诱导因子-1 α（HIF-1α）受损以及血管成熟有关。我们研究了血管生成素-1（Angiopoietin-1，Ang-1）基因治疗对db/db小鼠心肌HIF-1α稳定和血管成熟的潜在作用及其细胞内机制。研究设计和方法-对db/db小鼠全身施用腺病毒Ang-1（Ad-CMV-Ang-1）。检测心肌HIF-1α、血管内皮生长因子（VEGF）、血红素加氧酶-1（HO-1）、内皮型一氧化氮合酶（eNOS）、Akt和HIF-1α脯氨酰-4-羟化酶-2（PHD）2的表达。在梗死心肌的边缘区分析血管成熟、毛细血管和小动脉密度以及心脏间质纤维化。结果：全身给予Ad-CMV-Ang-1导致db/db小鼠心脏中Ang-1过表达。Ang-1基因治疗引起Akt和eNOS表达显著增加和HIF-1α稳定。这伴随着VEGF和HO-1表达的显著上调。有趣的是，Ang-1基因治疗也导致PHD 2表达的显著抑制。与野生型小鼠相比，db/db小鼠梗死心肌边缘区新生血管中的平滑肌募集和平滑肌覆盖严重受损。Ang-1基因治疗挽救了这些异常，导致缺血后14天毛细血管和小动脉密度急剧增加，心脏肥大和间质纤维化显著减少。总之，我们的数据表明，Ang-1促进心肌血管成熟和血管生成，同时抑制PHD 2和上调HIF-1α信号。结论：通过Ang-1基因治疗使未成熟血管正常化可能是治疗糖尿病相关心肌血管生成障碍的一种新的治疗策略。
OBJECTIVE— Diabetic impaired angiogenesis is associated with impairment of hypoxia-inducible factor-1α (HIF-1α) as well as vasculature maturation. We investigated the potential roles and intracellular mechanisms of angiopoietin-1 (Ang-1) gene therapy on myocardial HIF-1α stabilization and vascular maturation in db/db mice. RESEARCH DESIGN AND METHODS— db/db mice were systemically administrated adenovirus Ang-1 (Ad-CMV-Ang-1). Myocardial HIF-1α, vascular endothelial growth factor (VEGF), hemeoxygenase-1 (HO-1), endothelial nitric oxide synthase (eNOS), Akt, and HIF-1α–prolyl-4-hydroxylase-2 (PHD)2 expression were measured. Vasculature maturation, capillary and arteriole densities, and cardiac interstitial fibrosis were analyzed in the border zone of infarcted myocardium. RESULTS— Systemic administration of Ad-CMV-Ang-1 results in overexpression of Ang-1 in db/db mice hearts. Ang-1 gene therapy causes a significant increase in Akt and eNOS expression and HIF-1α stabilization. This is accompanied by a significant upregulation of VEGF and HO-1 expression. Intriguingly, Ang-1 gene therapy also leads to a significant inhibition of PHD2 expression. Smooth muscle recruitment and smooth muscle coverage in the neovessels of the border zone of infarcted myocardium are severely impaired in db/db mice compared with wild-type mice. Ang-1 gene therapy rescues these abnormalities, which leads to a dramatic increase in capillary and arteriole densities and a significant reduction of cardiac hypertrophy and interstitial fibrosis at 14 days after ischemia. Taken together, our data show that Ang-1 increases myocardial vascular maturation and angiogenesis together with suppression of PHD2 and the upregulation of HIF-1α signaling. CONCLUSIONS— Normalization of immature vasculature by Ang-1 gene therapy may represent a novel therapeutic strategy for treatment of the diabetes-associated impairment of myocardial angiogenesis.
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影响因子：
4.8
作者：
Berchner-Pfannschmidt, Utta;Yamac, Hatice;Fandrey, Joachim
通讯作者：
Fandrey, Joachim
DOI：
10.1152/ajpheart.01081.2005
发表时间：
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影响因子：
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作者：
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