CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes
CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes
复制标题
DOI：
10.1093/cvr/cvp369
复制
发表时间：
2010-03-01
影响因子：
10.8
通讯作者：
Pacher, Pal
中科院分区：
文献类型：
--
作者：
Mukhopadhyay, Partha;Rajesh, Mohanraj;Pacher, Pal
在这里，我们研究的机制，心血管CB 1大麻素受体可能会调节心功能不全，氧化应激，和相关的细胞死亡途径与急性/慢性心肌病引起的广泛使用的抗肿瘤化合物阿霉素（DOX）。通过分子生物学/生物化学方法和流式细胞术测量丝裂原活化蛋白激酶（MAPK）活化、细胞死亡标志物和氧化/亚硝化应激。DOX诱导野生型小鼠（CB 1 +/+）的左心室功能障碍、氧化/亚硝化应激加上受损的抗氧化防御、MAPK（p38和JNK）的激活以及心脏中的细胞死亡和/或纤维化，并且这些作用在CB 1敲除小鼠（CB 1-/-）中显著减弱。在表达CB 1受体的人原代心肌细胞中（通过RT-PCR、Western免疫印迹和流式细胞术证明），DOX、CB 1受体激动剂HU 210和内源性大麻素anandamide（AEA）同样诱导MAPK活化和细胞死亡。当DOX与CB 1激动剂AEA或HU 210共同给药时，DOX诱导的MAPK活化和细胞死亡显著增强。值得注意的是，由AEA、HU 210和DOX +/- AEA/HU 210诱导的细胞死亡和MAPK活化在很大程度上被CB 1拮抗剂（利莫那班和AM 281）或p38和JNK MAPK的抑制剂减弱。此外，AEA或HU 210在原代人心肌细胞中引发活性氧产生增加，当内源性大麻素合成或代谢途径因过度炎症和/或氧化/亚硝化应激而失调时，心肌细胞中CB 1的激活可能放大病理条件下的活性氧/氮-MAPK激活-细胞死亡途径，这可能有助于各种心血管疾病的病理生理学。
Here we investigated the mechanisms by which cardiovascular CB1 cannabinoid receptors may modulate the cardiac dysfunction, oxidative stress, and interrelated cell death pathways associated with acute/chronic cardiomyopathy induced by the widely used anti-tumour compound doxorubicin (DOX).Both load-dependent and -independent indices of left-ventricular function were measured by the Millar pressure-volume conductance system. Mitogen-activated protein kinase (MAPK) activation, cell-death markers, and oxidative/nitrosative stress were measured by molecular biology/biochemical methods and flow cytometry. DOX induced left-ventricular dysfunction, oxidative/nitrosative stress coupled with impaired antioxidant defense, activation of MAPK (p38 and JNK), and cell death and/or fibrosis in hearts of wide-type mice (CB1+/+), and these effects were markedly attenuated in CB1 knockouts (CB1-/-). In human primary cardiomyocytes expressing CB1 receptors (demonstrated by RT-PCR, western immunoblot, and flow cytometry) DOX, likewise the CB1 receptor agonist HU210 and the endocannabinoid anandamide (AEA), induced MAPK activation and cell death. The DOX-induced MAPK activation and cell death were significantly enhanced when DOX was co-administered with CB1 agonists AEA or HU210. Remarkably, cell death and MAPK activation induced by AEA, HU210, and DOX +/- AEA/HU210 were largely attenuated by either CB1 antagonists (rimonabant and AM281) or by inhibitors of p38 and JNK MAPKs. Furthermore, AEA or HU210 in primary human cardiomyocytes triggered increased reactive oxygen species generation.CB1 activation in cardiomyocytes may amplify the reactive oxygen/nitrogen species-MAPK activation-cell death pathway in pathological conditions when the endocannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, which may contribute to the pathophysiology of various cardiovascular diseases.