日前，山东大学教育部和卫生部心血管重构和功能研究重点实验室张运院士团队撰写的论文“血管紧张素转换酶2以血管壁细胞作为靶标减轻动脉粥样硬化病变”全文发表于国际著名的《美国国家科学院学报》（Proceedings of the National Academy of Sciences of the United States of America, 2010;107(36):15886-15891，IF 9.432）。张澄为该论文的第一作者，张运、董波和曹义海为该论文的联合通讯作者。

肾素-血管紧张素系统（RAS）是人体调节血压和血容量的重要系统，但在高血压、动脉粥样硬化和心力衰竭等多种心血管疾病时RAS过度激活，RAS中的血管紧张素转换酶（ACE）将血管紧张素I转化为血管紧张素II，后者是诱发和加重动脉粥样硬化的重要因子。血管紧张素转换酶2（ACE2）是近年来发现的与ACE结构相似的一种金属蛋白酶，可将血管紧张素II分解为血管紧张素1-7，后者可拮抗血管紧张素II，但是否具有抗动脉粥样硬化的作用尚不明了。在张运院士指导下，博士后研究人员董波与上海瑞金医院科研人员合作，成功地合成了携带小鼠ACE2基因的腺病毒载体，并应用于动脉粥样硬化成熟斑块兔模型的治疗。结果显示，ACE2过表达可显著减少斑块内巨噬细胞和脂质含量，增加斑块内平滑肌细胞和胶原纤维的含量，因而在国际上首次证明，ACE2过表达可稳定动脉粥样硬化斑块。这一研究发表在国际著名的《动脉硬化、血栓形成和血管生物学》杂志（Arteriosclerosis, Thrombosis and Vascular Biology, 2008;28(7): 1270-1276, IF 7.235）上。

在近期发表的PNAS论文中，张澄和董波博士在国际上首次证明，ACE2过表达可抑制实验兔的动脉粥样硬化的早期病变，其细胞机制是ACE2抑制了血管平滑肌细胞的增生和游移，改善了血管内皮细胞的功能，减轻了血管壁细胞的氧化应激和炎症反应，其分子机制是ACE2下调了血管壁细胞的ERK-p38、JAK-STAT和 Ang II-ROS-NF-κB信号通路，但上调了血管壁细胞的PI3K-Akt 信号通路。上述研究，为应用ACE2基因治疗动脉粥样硬化提供了崭新的途径。最近，张运团队在急性心肌梗死大鼠模型中心肌局部注射ACE2腺病毒载体，发现这一方法可显著减轻左室纤维化，改善左室重构和收缩功能，这一研究发表在《人类基因治疗》杂志（Human Gene Therapy, 2010, Epub ahead of print, IF 4.202）上。继之，他们将ACE2基因治疗的概念扩展至糖尿病肾病，发现ACE2可显著减轻糖尿病肾病大鼠的肾脏纤维化和氧化应激损伤，改善肾脏功能，这一研究发表在《分子医学》杂志（Molecular Medicine, 2010, Epub ahead of print, IF 5.02）上。这些系列研究，使山东大学在ACE2基因治疗的研究领域中达到了国际领先水平。

原文出处：

PNAS doi: 10.1073/pnas.1001253107

Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells

Cheng Zhanga, Yu Xia Zhaoa, Yue Hui Zhanga, Li Zhua, Bi Ping Denga, Zhao Li Zhoua, Shu Ying Lia, Xiao Ting Lua, Li Li Songa, Xue Ming Leia, Wen Bo Tanga, Nan Wanga, Chun Ming Panb, Huai Dong Songb, Chun Xi Liua, Bo Donga,c,1, Yun Zhanga,1, and Yihai Caod,1

aThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012, China;

bRuijin Hospital, Center of Molecular Medicine, Shanghai Institute of Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China;

cDepartment of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China; and

dDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden

Angiotensin-converting enzyme 2 (ACE2) is a newly discovered homolog of ACE whose actions oppose those of angiotensin II (AngII). However, the underlying mechanisms by which ACE2 effectively suppresses early atherosclerotic lesions remain poorly understood. Here, we show, both in vitro and in vivo, that ACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of vascular smooth muscle cells (VSMCs) and improving endothelial function. In a relatively large cohort animal study (66 rabbits), aortic segments transfected by Ad-ACE2 showed significantly attenuated fatty streak formation, neointimal macrophage infiltration, and alleviation of impaired endothelial function. Segments also showed decreased expression of monocyte chemoattractant protein 1, lectin-like oxidized low-density lipoprotein receptor 1, and proliferating cell nuclear antigen, which led to the delayed onset of atherosclerotic lesions. At the cellular level, ACE2 significantly modulated AngII-induced growth and migration in human umbilical vein endothelial cells and VSMCs. The antiatherosclerotic effect of ACE2 involved down-regulation of the ERK-p38, JAK-STAT, and AngII-ROS-NF-κB signaling pathways and up-regulation of the PI3K-Akt pathway. These findings revealed the molecular mechanisms of the antiatherosclerotic activity of ACE2 and suggested that modulation of ACE2 could offer a therapeutic option for treating atherosclerosis.