Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China.
Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2064-9. doi: 10.1073/pnas.1018925108. Epub 2011 Jan 18.
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.
VEGF 和血管生成素-1（Ang1）是两种主要的血管生成因子，正在被研究用于治疗心肌梗死（MI）。在缺血性心肌中靶向 VEGF 和 Ang1 的表达可以增加其局部治疗效果并降低可能的不良反应。腺相关病毒载体（AAV）表达心脏特异性和缺氧诱导的 VEGF[AAV-肌球蛋白轻链-2v（MLC）VEGF]和 Ang1（AAV-MLCAng1）被立即在结扎左冠状动脉前降支后即刻注射到猪心肌梗死周边区的六个不同部位。用 AAV-CMV（LacZ）或生理盐水注射等量的 AAV 到对照组动物。AAV 基因组除了心脏之外还在肝脏中被检测到。RT-PCR、Western blot 和 ELISA 分析显示，VEGF 和 Ang1 主要在梗死核心和梗死心脏边界的心肌中表达。门控单光子发射计算机断层扫描分析显示，与载体注射后 2 周相比，VEGF/Ang1 组在 8 周时具有更好的心脏功能和心肌灌注。与盐水和 LacZ 对照组相比，VEGF/Ang1 组在梗死区和梗死周边区表达更高的磷酸化 Akt 和 Bcl-xL，更少的 Caspase-3 和 Bad，更高的血管密度，更多的增殖性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 Ang1 的共表达通过诱导血管生成和心肌细胞增殖、激活生存途径和减少细胞凋亡来改善猪 MI 心脏的灌注和功能。
