Impaired Infarct Healing in Atherosclerotic Mice With Ly-6Chi Monocytosis

被引：274
作者：
Panizzi, Peter [1 ,4 ,5 ]
Swirski, Filip K. [1 ,4 ,5 ]
Figueiredo, Jose-Luiz [1 ,4 ,5 ]
Waterman, Peter [1 ,4 ,5 ]
Sosnovik, David E. [2 ,3 ,4 ,5 ]
Aikawa, Elena [4 ,5 ]
Libby, Peter [6 ]
Pittet, Mikael [1 ]
Weissleder, Ralph [1 ,4 ,5 ]
Nahrendorf, Matthias [1 ,4 ,5 ]
机构：
[1] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA
[2] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA
[3] Harvard Univ, Sch Med, Boston, MA USA
[4] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA USA
[5] Harvard Univ, Sch Med, Charlestown, MA USA
[6] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA
来源：
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 2010年 / 55卷 / 15期
基金：
美国国家卫生研究院;
关键词：
FMT; healing; heart failure; monocytes; myocardial infarction; ACUTE MYOCARDIAL-INFARCTION; LEFT-VENTRICULAR DYSFUNCTION; DISEASE; TRIAL; INFLAMMATION; REPERFUSION; MORTALITY; SUBSETS; INJURY;
D O I：
10.1016/j.jacc.2009.08.089
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
Objectives The aim of this study was to test whether blood monocytosis in mice with atherosclerosis affects infarct healing. Background Monocytes are cellular protagonists of tissue repair, and their specific subtypes regulate the healing program after myocardial infarction (MI). Inflammatory Ly-6C(hi) monocytes dominate on Day 1 to Day 4 and digest damaged tissue; reparative Ly-6C(lo) monocytes dominate on Day 5 to Day 10 and promote angiogenesis and scar formation. However, the monocyte repertoire is disturbed in atherosclerotic mice: Ly-6C(hi) monocytes expand selectively, which might disrupt the resolution of inflammation. Methods Ex vivo analysis of infarcts included flow cytometric monocyte enumeration, immunoactive staining, and quantitative polymerase chain reaction. To relate inflammatory activity to left ventricular remodeling, we used a combination of noninvasive fluorescence molecular tomography (FMT-CT) and physiologic imaging (magnetic resonance imaging). Results Five-day-old infarcts showed >10x more Ly-6C(hi) monocytes in atherosclerotic (apoE(-/-)) mice compared with wild-type mice. The injured tissue in apoE(-/-) mice also showed a more pronounced inflammatory gene expression profile (e.g., increased tumor necrosis factor-alpha and myeloperoxidase and decreased transforming growth factor-beta) and a higher abundance of proteases, which are associated with the activity of Ly-6C(hi) monocytes. The FMT-CT on Day 5 after MI showed higher proteolysis and phagocytosis in infarcts of atherosclerotic mice. Serial magnetic resonance imaging showed accelerated deterioration of ejection fraction between Day 1 and Day 21 after MI in apoE(-/-). Finally, we could recapitulate these features in wild-type mice with artificially induced Ly-6C(hi) monocytosis. Conclusions Ly-6C(hi) monocytosis disturbs resolution of inflammation in murine infarcts and consequently enhances left ventricular remodeling. These findings position monocyte subsets as potential therapeutic targets to augment tissue repair after infarction and to prevent post-MI heart failure. (J Am Coll Cardiol 2010;55:1629-38) (C) 2010 by the American College of Cardiology Foundation
引用
收藏
页码：1629 / 1638
页数：10
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