《美国科学院院刊》（Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2064-9.）发表南京医科大学第一附属医院心脏科杨志健教授的论文， 题为“血管内皮生长因子和血管生成素-1表达共促进急性心肌梗死心脏血管生成和心肌细胞增生、减少心肌细胞凋亡”，为缺血性心脏病患者提供了全新的治疗策略。
心肌梗死是一类严重威胁人类健康的急重症。在我国，缺血性心脏病死亡率呈明显上升趋势，传统治疗方法包括药物治疗、血管介入成形术和外科冠脉旁路移植术，这些方法虽然明显提高了心肌梗死的生存率和生活质量，但对坏死心肌作用有限，尤其对弥漫性冠状动脉病变难以奏效，心肌梗死已成为心力衰竭的首要原因。因此，亟需积极探索心肌梗死新的治疗策略和方法。治疗性血管新生又称“分子搭桥术”或“生物搭桥术”，为缺血性心脏病病人提供了全新的治疗策略。目前治疗性血管新生的方法主要包括蛋白治疗、细胞治疗和基因治疗等。多种血管生长因子，如血管内皮生长因子、成纤维细胞生长因子、血管生成素和肝细胞生长因子等能诱导缺血心肌血管新生并改善心脏功能。虽然生血管因子基因治疗缺血性心脏病的研究成果令人鼓舞，但未调控生血管因子在心脏外脏器的过度表达大大降低生血管因子基因治疗缺血性心脏病的安全性，是目前生血管因子基因治疗心肌梗死面临的重要科学问题。
杨志健教授对基因治疗缺血性心脏病的基因表达调控进行了积极探索，该研究应用MLC-2v启动子和HRE(hypoxia responsive element)调控VEGF和angiopoietin-1在心肌缺血区的特异表达，利用VEGF和angiopoietin-1不同生血管机制治疗缺血性心脏病。研究结果显示，MLC-2v启动子和HRE调控VEGF和angiopoietin-1高表达在心肌梗死区和梗死移行区，高表达的VEGF和angiopoietin-1通过抗心肌凋亡和促进血管新生改善心肌灌注和心脏功能；此外，首次发现VEGF和angiopoietin-1能够通过激活Akt激酶与上调cyclin D2/cdk4和cyclin A/cdk2的表达促进心肌细胞的增生。论文第一作者陶正贤博士曾应邀参加美国基因治疗11届年会并作大会报告，宣读了该研究部分结果。该研究对于调控生血管基因在缺血心肌的特异表达，提高生血管基因治疗缺血性心脏病安全性具有重要意义。
杨志健教授十几年来一直从事缺血性心脏病生物学治疗研究，于2006年曾在Gene Therapy上发表论文：骨髓来源的间充质干细胞联合肝细胞生长因子经非梗死相关动脉治疗急性心肌梗死的实验研究。近年来，和中国人民解放军军事科学院合作，进行肝细胞生长因子治疗缺血性心脏病的基础和临床研究，已完成Ⅰ期临床研究，现正开展Ⅱ期临床研究，从已经完成的3例缺血性心脏病患者随访结果看，都达到预期治疗效果。“在心血管领域，肝细胞生长因子是目前唯一进入临床研究的一类新药。”杨教授说，“肝细胞生长因子有望成为中国第一个治疗缺血性心脏病的基因治疗新药，将为缺血性心脏病患者带来新的曙光。”
该研究成果得到了国家自然科学基金（项目编号：30971254，项目名称：TnIc和HRE调控HGF在缺血心肌特异表达对猪心肌灌注与心功能的影响）、江苏省科技厅创新学者攀登项目、江苏省卫生厅重点项目长期以来的支持。（生物谷Bioon.com）
生物谷推荐原文出处：
Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2064-9. Epub 2011 Jan 18.
Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart.
Tao Z, Chen B, Tan X, Zhao Y, Wang L, Zhu T, Cao K, Yang Z, Kan YW, Su H.
SourceDepartment of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China.
Abstract
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.
