Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart
Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart
复制标题
VEGF 和 angiopoietin-1 共表达促进血管生成和心肌细胞增殖，减少猪心肌梗死 (MI) 心脏的细胞凋亡
DOI：
10.1073/pnas.1018925108
复制
发表时间：
2011-02-01
影响因子：
11.1
通讯作者：
Su, Hua
中科院分区：
文献类型：
--
作者：
Tao, Zhengxian;Chen, Bo;Su, Hua
血管内皮生长因子和血管生成素-1（Ang 1）是两个主要的血管生成因子，正在研究用于治疗心肌梗死（MI）。靶向VEGF和Ang 1在缺血心肌中的表达可以增加其局部治疗效果并减少可能的不良反应。将表达心肌特异性和缺氧诱导性VEGF [AAV-myosin light chain-2 v（MLC）VEGF]和Ang 1（AAV-MLCAng 1）的腺相关病毒载体（AAV）共注射（VEGF/Ang 1组）于结扎左冠状动脉降支后即刻的猪心肌梗死周围区的6个不同部位。将相同剂量的AAV-巨细胞病毒（CMV）LacZ或盐水注射到对照动物中。除了心脏之外，还在肝脏中检测到AAV基因组。RT-PCR、Western blotting和ELISA分析显示VEGF和Ang 1主要表达于梗死核心和梗死边缘的心肌。门控单光子发射计算机断层扫描分析显示，VEGF/Ang 1组在8周时的心功能和心肌灌注优于载体注射后2周。与生理盐水和LacZ对照组相比，VEGF/Ang 1组表达更高的磷酸化Akt和Bcl-xL，更少的Caspase-3和Bad，并且在梗死区和梗死周围区具有更高的血管密度，更多的增殖心肌细胞和更少的凋亡细胞。因此，心脏特异性和缺氧诱导的VEGF和Ang 1的共表达通过诱导血管生成和心肌细胞增殖、激活促存活途径和减少细胞凋亡来改善猪MI心脏的灌注和功能。
VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac-specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis.