Department of Cardiac Surgery, University Clinical Centre Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
Basic Res Cardiol. 2014 Jul;109(4):425. doi: 10.1007/s00395-014-0425-x. Epub 2014 Jul 1.
Ischemic heart disease is associated with inflammation, interstitial fibrosis and ventricular dysfunction prior to the development of heart failure. Endocannabinoids and the cannabinoid receptor CB2 have been claimed to be involved, but their potential role in cardioprotection is not well understood. We therefore explored the role of the cannabinoid receptor CB2 during the initial phase of ischemic cardiomyopathy development prior to the onset of ventricular dysfunction or infarction. Wild type and CB2-deficient mice underwent daily brief, repetitive ischemia and reperfusion (I/R) episodes leading to ischemic cardiomyopathy. The relevance of the endocannabinoid-CB2 receptor axis was underscored by the finding that CB2 was upregulated in ischemic wild type cardiomyocytes and that anandamide level was transiently increased during I/R. CB2-deficient mice showed an increased rate of apoptosis, irreversible loss of cardiomyocytes and persistent left ventricular dysfunction 60 days after the injury, whereas wild type mice presented neither morphological nor functional defects. These defects were due to lack of cardiomyocyte protection mechanisms, as CB2-deficient hearts were in contrast to controls unable to induce switch in myosin heavy chain isoforms, antioxidative enzymes and chemokine CCL2 during repetitive I/R. In addition, a prolonged inflammatory response and adverse myocardial remodeling were found in CB2-deficient hearts because of postponed activation of the M2a macrophage subpopulation. Therefore, the endocannabinoid-CB2 receptor axis plays a key role in cardioprotection during the initial phase of ischemic cardiomyopathy development.
缺血性心脏病与炎症、间质纤维化和心室功能障碍有关，这些病变在心力衰竭发生之前就已经存在。内源性大麻素和大麻素受体 CB2 据称参与其中，但它们在心脏保护中的潜在作用尚不清楚。因此，我们在缺血性心肌病发展的初始阶段，即在心室功能障碍或梗塞发生之前，探讨了大麻素受体 CB2 的作用。野生型和 CB2 缺陷型小鼠每天接受短暂的、重复的缺血再灌注（I/R），导致缺血性心肌病。内源性大麻素-CB2 受体轴的相关性是由以下发现强调的：CB2 在缺血性野生型心肌细胞中上调，并且在 I/R 期间，花生四烯酸水平短暂增加。CB2 缺陷型小鼠的细胞凋亡率增加，心肌细胞不可逆丢失和左心室功能持续障碍 60 天后，而野生型小鼠既没有形态学也没有功能缺陷。这些缺陷是由于缺乏心肌细胞保护机制，因为 CB2 缺陷型心脏与对照相比，在重复 I/R 期间不能诱导肌球蛋白重链同工型、抗氧化酶和趋化因子 CCL2 的转换。此外，由于 M2a 巨噬细胞亚群的激活推迟，CB2 缺陷型心脏中发现了延长的炎症反应和不良的心肌重构。因此，内源性大麻素-CB2 受体轴在缺血性心肌病发展的初始阶段的心脏保护中发挥着关键作用。
