Duerr Georg D, Heinemann Jan C, Gestrich Christopher, Heuft Tobias, Klaas Timo, Keppel Katharina, Roell Wilhelm, Klein Alexandra, Zimmer Andreas, Velten Markus, Kilic Ana, Bindila Laura, Lutz Beat, Dewald Oliver
Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
Institute of Physiology I, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
Life Sci. 2015 Oct 1;138:8-17. doi: 10.1016/j.lfs.2014.11.005. Epub 2014 Nov 14.
Reperfusion ofmyocardial infarction is associated with inflammatory reaction and subsequentmyocardial remodeling with a rapid scar formation in mice. The cannabinoid receptor CB2 has been associated with cardioprotection and regulation ofmacrophage function.Weinvestigated its role in remodeling of reperfused infarction.
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 endocannabinoidswas determined using liquid chromatography-multiple reaction monitoring.
In contrast to a rapid formation of granulation tissue and a compacted non-transmural scar inWT mice after 7 days of reperfusion, Cnr2−/− mice showed a non-compacted transmural scar. Millar® 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-Iα or lysil oxidase, thereby indicating adversemyocardial remodeling.
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.
心肌梗死再灌注与炎症反应以及随后小鼠心肌重塑和快速瘢痕形成有关。大麻素受体CB2与心脏保护和巨噬细胞功能调节有关。我们研究了其在再灌注梗死重塑中的作用。
在野生型C57/BL6J（WT）和CB2受体缺陷（Cnr2−/−）小鼠（每组n = 8）中，进行1小时的左前降支闭塞，随后分别再灌注6小时、1天、3天和7天。对心脏进行功能、形态学和mRNA/蛋白质分析，并使用液相色谱 - 多反应监测测定内源性大麻素的组织浓度。
与WT小鼠再灌注7天后肉芽组织快速形成和致密的非透壁瘢痕不同，Cnr2−/−小鼠表现出非致密的透壁瘢痕。Millar®左心室导管测量显示Cnr2−/−小鼠的心功能明显更差。我们发现Cnr2−/−心脏中内源性大麻素浓度没有代偿性升高。与WT心脏相比，Cnr2−/−心脏中的巨噬细胞浸润明显更强，并且还影响了远隔的间隔。我们发现Cnr2−/−心脏中存在细胞因子驱动的炎症反应，但趋化因子没有明显诱导。血小板反应蛋白-1的免疫组织化学显示Cnr2−/−心脏中梗死边界区形成功能失调。Cnr2−/−心脏中肌腱蛋白C、胶原蛋白-Iα或赖氨酰氧化酶没有明显诱导，从而表明心肌重塑不良。
内源性大麻素通过CB2受体调节梗死后的炎症反应和心肌重塑。CB2受体在梗死边界区形成、胶原沉积和重塑过程中稳定瘢痕的组织化中起重要作用。
