Maegdefessel Lars, Spin Joshua M, Raaz Uwe, Eken Suzanne M, Toh Ryuji, Azuma Junya, Adam Matti, Nakagami Futoshi, Heymann Helen M, Chernogubova Ekaterina, Jin Hong, Roy Joy, Hultgren Rebecka, Caidahl Kenneth, Schrepfer Sonja, Hamsten Anders, Eriksson Per, McConnell Michael V, Dalman Ronald L, Tsao Philip S
1] Division of Cardiovascular Medicine, Stanford University, Falk CVRB, 300 Pasteur Drive, Stanford, California 94305, USA [2] Center for Molecular Medicine L8:03, Department of Medicine, Karolinska Institute and University Hospital, Stockholm 17176, Sweden.
1] Division of Cardiovascular Medicine, Stanford University, Falk CVRB, 300 Pasteur Drive, Stanford, California 94305, USA [2] VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304, USA.
Nat Commun. 2014 Oct 31;5:5214. doi: 10.1038/ncomms6214.
Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans.
腹主动脉瘤（AAA）的识别与治疗仍是血管医学领域最突出的挑战之一。微小RNA（miRNA）是心血管病理过程的关键调节因子，也是限制AAA扩张的有趣靶点。在此，我们通过使用两种已建立的AAA疾病小鼠模型以及人体主动脉组织和血浆分析表明，miR-24是血管炎症和AAA病理过程的关键调节因子。体内和体外研究表明，几丁质酶3样1（Chi3l1）是受miR-24调控的主要靶点和效应因子，它调节巨噬细胞中的细胞因子合成及其存活，促进主动脉平滑肌细胞迁移和细胞因子产生，并刺激血管内皮细胞中黏附分子的表达。我们进一步表明，miR-24的调节会改变动物模型中AAA的进展，并且miR-24和CHI3L1代表了人类AAA疾病进展的新型血浆生物标志物。
