The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy
The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy
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DOI：
10.1096/fj.09-129478
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发表时间：
2009-07-01
期刊：
影响因子：
4.8
通讯作者：
Pavoine, Catherine
中科院分区：
文献类型：
--
作者：
Defer, Nicole;Wan, Jinghong;Pavoine, Catherine
心肌梗死后（MI）心力衰竭是西方国家的一个主要公共卫生问题，是由缺血/再灌注（IR）诱导的细胞死亡、重塑和收缩功能障碍引起的。体外研究表明，大麻素2型（CB2）受体激动剂在IR后数小时内具有心脏保护抗炎作用。在此，我们评估了CB2受体对ir诱导的细胞死亡、纤维化和心功能障碍的体内作用，并研究了心肌细胞和成纤维细胞的靶作用。与野生型（WT）心脏相比，CB2（-/-）心脏在IR后24小时梗死面积增加，再灌注时注射CB2激动剂JWH133 （3mg /kg）时梗死面积减少。与WT心脏相比，CB2（-/-）心脏在IR后3 d表现出广泛的损伤，细胞凋亡和重塑增强影响远端心肌。最后，CB2（-/-）型心脏表现出纤维化加剧，与IR后4周的左心室功能障碍相关，而WT型心脏则恢复正常功能。从CB2（-/-）心脏分离的心肌细胞和成纤维细胞表现出比WT细胞更高的h2o2诱导死亡，而1 μ M JWH133可触发存活效应。此外，与WT细胞相比，h2o2诱导的CB2（-/-）成纤维细胞活化增加，而1 μ M jwh133处理的WT成纤维细胞活化减少。因此，CB2受体激活可能通过直接抑制心肌细胞和成纤维细胞死亡以及防止成纤维细胞活化来预防ir后心力衰竭。-Defer， N., Wan， J., Souktani， R., Escoubet， B., Perier， M., Caramelle， P., Manin， S., Deveaux， V., Bourin， M.- c。peker， F., Pavoine， C.大麻素受体2型可促进心肌细胞和成纤维细胞的存活，并可预防缺血/再灌注诱导的心肌病。杂志23,2120-2130 （2009）
Post-myocardial infarction (MI) heart failure is a major public health problem in Western countries and results from ischemia/reperfusion (IR)-induced cell death, remodeling, and contractile dysfunction. Ex vivo studies have demonstrated the cardioprotective anti-inflammatory effect of the cannabinoid type 2 (CB2) receptor agonists within hours after IR. Herein, we evaluated the in vivo effect of CB2 receptors on IR-induced cell death, fibrosis, and cardiac dysfunction and investigated the target role of cardiac myocytes and fibroblasts. The infarct size was increased 24 h after IR in CB2(-/-) vs. wild-type (WT) hearts and decreased when WT hearts were injected with the CB2 agonist JWH133 (3 mg/kg) at reperfusion. Compared with WT hearts, CB2(-/-) hearts showed widespread injury 3 d after IR, with enhanced apoptosis and remodeling affecting the remote myocardium. Finally, CB2(-/-) hearts exhibited exacerbated fibrosis, associated with left ventricular dysfunction 4 wk after IR, whereas their WT counterparts recovered normal function. Cardiac myocytes and fibroblasts isolated from CB2(-/-) hearts displayed a higher H2O2-induced death than WT cells, whereas 1 mu M JWH133 triggered survival effects. Furthermore, H2O2-induced myofibroblast activation was increased in CB2(-/-) fibroblasts but decreased in 1 mu M JWH133-treated WT fibroblasts, compared with that in WT cells. Therefore, CB2 receptor activation may protect against post-IR heart failure through direct inhibition of cardiac myocyte and fibroblast death and prevention of myofibroblast activation.-Defer, N., Wan, J., Souktani, R., Escoubet, B., Perier, M., Caramelle, P., Manin, S., Deveaux, V., Bourin, M.-C., Zimmer, A., Lotersztajn, S., Pecker, F., Pavoine, C. The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy. FASEB J. 23, 2120-2130 (2009)