Impaired border zone formation and adverse remodeling after reperfused myocardial infarction in cannabinoid CB2 receptor deficient mice

被引：23
作者：
Duerr, Georg D. [1 ]
Heinemann, Jan C. [1 ]
Gestrich, Christopher [1 ]
Heuft, Tobias [1 ]
Klaas, Timo [1 ]
Keppel, Katharina [1 ]
Roell, Wilhelm [1 ]
Klein, Alexandra [2 ]
Zimmer, Andreas [3 ]
Velten, Markus [4 ]
Kilic, Ana [5 ]
Bindila, Laura [6 ]
Lutz, Beat [6 ]
Dewald, Oliver [1 ]
机构：
[1] Univ Clin Ctr Bonn, Dept Cardiac Surg, D-53105 Bonn, Germany
[2] Univ Bonn, Inst Physiol 1, Life & Brain Ctr, D-53105 Bonn, Germany
[3] Life & Brain Ctr, Inst Mol Psychiat, D-53105 Bonn, Germany
[4] Univ Clin Ctr Bonn, Dept Anesthesiol, D-53105 Bonn, Germany
[5] Univ Bonn, Inst Pharmacol & Toxicol, Biomed Ctr, D-53105 Bonn, Germany
[6] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55128 Mainz, Germany
来源：
LIFE SCIENCES | 2015年 / 138卷
关键词：
Ischemia; Reperfusion; Thrombospondin; Infarction border zone; Endocannabinoids; ISCHEMIC CARDIOMYOPATHY; INFLAMMATORY RESPONSE; HEART; THROMBOSPONDIN-1; PROTECTS; MODEL;
D O I：
10.1016/j.lfs.2014.11.005
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
Aims: Reperfusion of myocardial infarction is associated with inflammatory reaction and subsequent myocardial remodeling with a rapid scar formation in mice. The cannabinoid receptor CB2 has been associated with cardioprotection and regulation of macrophage function. We investigated its role in remodeling of reperfused infarction. Main methods: One hour LAD-occlusion was followed by reperfusion over 6 h and 1,3 and 7 days in wild-type C57/BL6J (WT) and CB2 receptor-deficient (Cnr2(-/-)) mice (n = 8/group). Hearts were processed for functional, morphological and mRNA/protein analysis, and tissue concentration of endocannabinoids was determined using liquid chromatography-multiple reaction monitoring. Key findings: In contrast to a rapid formation of granulation tissue and a compacted non-transmural scar in WT mice after 7 days of reperfusion, Cnr2(-/-) mice showed a non-compacted transmural scar. Millar (R) left ventricular catheter measurements revealed a significantly worse function in Cnr2(-/-) mice. We found no compensatory elevation of endocannabinoid concentration in Cnr2(-/-) hearts. Macrophage infiltration was significantly stronger in Cnr2(-/-) hearts and affected also the remote septum, when compared to WT hearts. We found a cytokine-driven inflammatory response in Cnr2(-/-) hearts with no significant induction of chemokines. Immunohistochemistry for thrombospondin-1 revealed a dysfunctional infarction border zone formation in Cnr2(-/-) hearts. Cnr2(-/-) hearts showed no significant induction of tenascin C, collagen-la or lysil oxidase, thereby indicating adverse myocardial remodeling. Significance: Endocannabinoids act via CB2 receptor in the modulation of inflammatory response and myocardial remodeling after infarction. CB2 receptor plays an important role in the formation of infarction border zone, collagen deposition and organization of stable scar during remodeling. (C) 2014 Elsevier Inc All rights reserved.
引用
收藏
页码：8 / 17
页数：10
相关论文
共 27 条
[1]   Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor [J].
Buckley , NE ;
McCoy, KL ;
Mezey, É ;
Bonner, T ;
Zimmer, A ;
Felder, CC ;
Glass, M ;
Zimmer, A .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2000, 396 (2-3) :141-149
[2]   The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy [J].
Defer, Nicole ;
Wan, Jinghong ;
Souktani, Richard ;
Escoubet, Brigitte ;
Perier, Magali ;
Caramelle, Philippe ;
Manin, Sylvie ;
Deveaux, Vanessa ;
Bourin, Marie-Claude ;
Zimmer, Andreas ;
Lotersztajn, Sophie ;
Pecker, Francoise ;
Pavoine, Catherine .
FASEB JOURNAL, 2009, 23 (07) :2120-2130
[3]   Of mice and dogs: Species-specific differences in the inflammatory response following myocardial infarction [J].
Dewald, O ;
Ren, GF ;
Duerr, GD ;
Zoerlein, M ;
Klemm, C ;
Gersch, C ;
Tincey, S ;
Michael, LH ;
Entman, ML ;
Frangogiannis, NG .
AMERICAN JOURNAL OF PATHOLOGY, 2004, 164 (02) :665-677
[4]   CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts [J].
Dewald, O ;
Zymek, P ;
Winkelmann, K ;
Koerting, A ;
Ren, GF ;
Abou-Khamis, T ;
Michael, LH ;
Rollins, BJ ;
Entman, ML ;
Frangogiannis, NG .
CIRCULATION RESEARCH, 2005, 96 (08) :881-889
[5]   A murine model of ischemic cardiomyopathy induced by repetitive ischemia and reperfusion [J].
Dewald, O ;
Frangogiannis, NG ;
Zoerlein, MP ;
Duerr, GD ;
Taffet, G ;
Michael, LH ;
Welz, A ;
Entman, ML .
THORACIC AND CARDIOVASCULAR SURGEON, 2004, 52 (05) :305-311
[6]   Development of murine ischemic cardiomyopathy is associated with a transient inflammatory reaction and depends on reactive oxygen species [J].
Dewald, O ;
Frangogiannis, NG ;
Zoerlein, M ;
Duerr, GD ;
Klemm, C ;
Knuefermann, P ;
Taffet, G ;
Michael, LH ;
Crapo, JD ;
Welz, A ;
Entman, ML .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (05) :2700-2705
[7]   The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy [J].
Duerr, Georg D. ;
Heinemann, Jan C. ;
Suchan, Georg ;
Kolobara, Elvis ;
Wenzel, Daniela ;
Geisen, Caroline ;
Matthey, Michaela ;
Passe-Tietjen, Kristine ;
Mahmud, Walid ;
Ghanem, Alexander ;
Tiemann, Klaus ;
Alferink, Judith ;
Burgdorf, Sven ;
Buchalla, Rainer ;
Zimmer, Andreas ;
Lutz, Beat ;
Welz, Armin ;
Fleischmann, Bernd K. ;
Dewald, Oliver .
BASIC RESEARCH IN CARDIOLOGY, 2014, 109 (04)
[8]   Cardiomyocyte specific peroxisome proliferator-activated receptor-α overexpression leads to irreversible damage in ischemic murine heart [J].
Duerr, Georg D. ;
Heinemann, Jan C. ;
Arnoldi, Vanessa ;
Feisst, Andreas ;
Kley, Julian ;
Ghanem, Alexander ;
Welz, Armin ;
Dewald, Oliver .
LIFE SCIENCES, 2014, 102 (02) :88-97
[9]   Comparison of Myocardial Remodeling between Cryoinfarction and Reperfused Infarction in Mice [J].
Duerr, Georg D. ;
Elhafi, Naziha ;
Bostani, Toktam ;
Ellinger, Joerg ;
Swieny, Louay ;
Kolobara, Elvis ;
Welz, Armin ;
Dewald, Oliver .
JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY, 2011,
[10]   Cardiac specific expression of the green fluorescent protein during early murine embryonic development [J].
Fleischmann, M ;
Bloch, W ;
Kolossov, E ;
Andressen, C ;
Müller, M ;
Brem, G ;
Hescheler, J ;
Addicks, K ;
Fleischmann, BK .
FEBS LETTERS, 1998, 440 (03) :370-376
123