The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy
The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy
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DOI：
10.1007/s00395-014-0425-x
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发表时间：
2014-07-01
影响因子：
9.5
通讯作者：
Dewald, Oliver
中科院分区：
文献类型：
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作者：
Duerr, Georg D.;Heinemann, Jan C.;Dewald, Oliver
在心力衰竭发展之前，缺血性心脏病与炎症、间质纤维化和心功能不全有关。内源性大麻素和大麻素受体CB2已经被声称参与了这一过程，但它们在心脏保护中的潜在作用并不是很清楚。因此，我们探讨了大麻素受体CB2在心功能不全或脑梗塞发生之前的缺血性心肌病发展的初始阶段中的作用。野生型和CB2缺陷小鼠每天经历短暂、重复的缺血和再灌注(I/R)发作，导致缺血性心肌病。发现CB2在缺血的野生型心肌细胞中表达上调，在I/R期间ANANDAME水平一过性增加，这突显了内源性大麻素-CB2受体轴的相关性。CB2缺乏的小鼠在损伤60d后显示出更高的凋亡率、心肌细胞的不可逆性丢失和持续性的左心功能障碍，而野生型小鼠则没有表现出形态和功能上的缺陷。这些缺陷是由于缺乏心肌细胞保护机制，因为CB2缺乏的心脏与对照组相比，无法在重复I/R期间诱导肌球蛋白重链异构体、抗氧化酶和趋化因子CCL2的转换。此外，由于延迟激活M2a巨噬细胞亚群，CB2缺乏的心脏发现持续的炎症反应和不利的心肌重构。因此，内源性大麻素-CB2受体轴在缺血性心肌病发病初期的心肌保护中起着关键作用。
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.