CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia
CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia
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DOI：
10.1016/j.yjmcc.2015.06.010
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发表时间：
2015-08-01
影响因子：
5
通讯作者：
Shih, Chun-Che
中科院分区：
文献类型：
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作者：
Lin, Chih-Yuan;Hsu, Yu-Juei;Shih, Chun-Che
大麻素受体1（CB 1 R）在尿毒症心肌病心肌肥厚和纤维化的发生发展中起重要作用。然而，CB 1 R是否参与尿毒症心肌病的发病机制仍不清楚。在这里，我们的目的是阐明CB 1 R通过调节Akt信号在尿毒症心肌病的发展中的作用。在用CB 1 R拮抗剂CB 1 R治疗的5/6肾切除慢性肾病（CKD）小鼠中，分别通过超声心动图和免疫组织化学染色评估心脏大小和心肌纤维化，并通过免疫印迹法测定暴露于尿毒症毒素硫酸吲哚酚（IS）的H9 c2细胞中的纤维化标志物表达水平，用有机阴离子转运蛋白1抑制剂或CB 1 R拮抗剂或激动剂也评估Akt磷酸化，以检查H9 c2细胞中IS诱导的CB 1 R活化的下游信号通路。CKD小鼠表现出明显的左心室肥大和心肌纤维化，这是逆转与CB 1 R拮抗剂治疗。CB 1 R，胶原蛋白I，转化生长因子（TGF）-β，和α-平滑肌肌动蛋白（SMA）的表达表现出时间和剂量依赖性上调与IS处理的H9 c2细胞。通过CB 1 R拮抗剂或小干扰RNA介导的敲低来抑制CB 1 R可减弱IS处理的H9 c2细胞中I型胶原、TGF-β和α-SMA的表达，而在这些细胞中，CB 1 R激动剂增强Akt磷酸化，而CB 1 R拮抗剂消除Akt磷酸化。总之，我们得出结论，CB 1 R阻断减弱CKD小鼠模型中LVH和Akt介导的心脏纤维化。尿毒症毒素IS刺激CB 1 R和纤维化标志物的表达，并且CB 1 R抑制通过调节H9 c2肌成纤维细胞中的Akt信号传导发挥抗纤维化作用。因此，开发针对CB 1 R的药物可能对尿毒症心肌病的治疗具有潜在的意义。(C)2015爱思唯尔有限公司版权所有。
Cannabinoid receptor type 1 (CB1R) plays an important role in the development of myocardial hypertrophy and fibrosis-2 pathological features of uremic cardiomyopathy. However, it remains unknown whether CB1R is involved in the pathogenesis of uremic cardiomyopathy. Here, we aimed to elucidate the role of CB1R in the development of uremic cardiomyopathy via modulation of Akt signalling. The heart size and myocardial fibrosis were evaluated by echocardiography and immunohistochemical staining, respectively, in 5/6 nephrectomy chronic kidney disease (CKD) mice treated with a CB1R antagonist CB1R and fibrosis marker expression levels were determined by immunoblotting in H9c2 cells exposed to the uremic toxin indoxyl sulfate (IS), with an organic anion transporter 1 inhibitor or a CB1R antagonist or agonist Akt phosphorylation was also assessed to examine the signaling pathways downstream of CB1R activation induced by IS in H9c2 cells. CKD mice exhibited marked left ventricular hypertrophy and myocardial fibrosis, which were reversed by treatment with the CB1R antagonist. CB1R, collagen I, transforming growth factor (TGF)-beta, and alpha-smooth muscle actin (SMA) expression showed time- and dose-dependent upregulation in H9c2 cells treated with IS. The inhibition of CB1R by either CB1R antagonist or small interfering RNA-mediated knockdown attenuated the expression of collagen I, TGF-beta, and alpha-SMA in IS-treated H9c2 cells, while Akt phosphorylation was enhanced by CB1R agonist and abrogated by CB1R antagonist in these cells. In summary, we conclude that CB1R blockade attenuates LVH and Akt-mediated cardiac fibrosis in a CKD mouse model. Uremic toxin IS stimulates the expression of CB1R and fibrotic markers and CB1R inhibition exerts anti-fibrotic effects via modulation of Akt signaling in H9c2 myofibroblasts. Therefore, the development of drugs targeting CB1R may have therapeutic potential in the treatment of uremic cardiomyopathy. (C) 2015 Elsevier Ltd. All rights reserved.