Celastrol-Induced Suppression of the MiR-21/ERK Signalling Pathway Attenuates Cardiac Fibrosis and Dysfunction
Celastrol-Induced Suppression of the MiR-21/ERK Signalling Pathway Attenuates Cardiac Fibrosis and Dysfunction
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雷公藤红素诱导的 MiR-21/ERK 信号通路抑制可减轻心脏纤维化和功能障碍
DOI：
10.1159/000445554
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发表时间：
2016-01-01
影响因子：
--
通讯作者：
Zhang, Cuntai
中科院分区：
文献类型：
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作者：
Cheng, Mian;Wu, Gang;Zhang, Cuntai
背景：心肌纤维化导致心肌重塑和功能障碍。雷公藤红素是一种传统的东方药物，被认为具有心脏保护作用。然而，其潜在机制尚不清楚。本研究探讨雷公藤红素预防心脏纤维化和功能障碍的能力，并探讨其潜在机制。方法：采用心肌纤维化动物模型和细胞模型。用横主动脉缩窄法（TAC）诱导小鼠心肌纤维化。根据组织学和生物化学测量评价心脏肥大和纤维化。超声心动图评价心功能。采用Western blotting检测转化生长因子β 1（TGF-β1）、细胞外信号调节激酶1/2（ERK 1/2）信号转导水平，采用实时定量PCR检测miR-21的表达。在体外研究中，用TGF-β1处理培养的心脏成纤维细胞（CF）并用microRNA-21（miR 21）转染。结果如下：Celastrol治疗可减少胶原沉积，下调α-平滑肌肌动蛋白（α-SMA）、心房利钠肽（ANP）、脑利钠肽（BNP）、β-肌球蛋白重链（β-MHC）、miR-21和p-ERK/ERK。在TAC小鼠模型中，雷公藤红素治疗显著减轻了心脏功能障碍。雷公藤红素处理降低了体外培养CFs的心肌成纤维细胞活力和胶原含量，下调了α-SMA。雷公藤红素还抑制miR-21/ERK信号通路。雷公藤红素可减弱TGF-β1对miR-21的上调作用，并降低转染miR-21的CFs中p-ERK/ERK水平的升高。结论：MiR-21/ERK信号通路可能是预防心肌纤维化的潜在治疗途径。雷公藤红素可改善心肌纤维化和心功能不全，可能与体内外miR-21/ERK信号通路有关。
Backgroud: Myocardial fibrosis results in myocardial remodelling and dysfunction. Celastrol, a traditional oriental medicine, has been suggested to have cardioprotective effects. However, its underlying mechanism is unknown. This study investigated the ability of celastrol to prevent cardiac fibrosis and dysfunction and explored the underlying mechanisms. Methods: Animal and cell models of cardiac fibrosis were used in this study. Myocardial fibrosis was induced by transverse aortic constriction (TAC) in mice. Cardiac hypertrophy and fibrosis were evaluated based on histological and biochemical measurements. Cardiac function was evaluated by echocardiography. The levels of transforming growth factor beta 1 (TGF-β1), extracellular signal regulated kinases 1/2 (ERK1/2) signalling were measured using Western blotting, while the expression of miR-21was analyzed by real-time qRT-PCR in vitro and in vivo. In vitro studies, cultured cardiac fibroblasts (CFs) were treated with TGF-β1 and transfected with microRNA-21(miR21). Results: Celastrol treatment reduced the increased collagen deposition and down-regulated α-smooth muscle actin (α-SMA), atrial natriuretic peptide (ANP), brain natriuretic peptides (BNP), beta-myosin heavy chain (β-MHC), miR-21 and p-ERK/ERK. Cardiac dysfunction was significantly attenuated by celastrol treatment in the TAC mice model. Celastrol treatment reduced myocardial fibroblast viability and collagen content and down-regulated α-SMA in cultured CFs in vitro. Celastrol also inhibited the miR-21/ERK signalling pathway. Celastrol attenuated miR-21 up-regulation by TGF-β1 and decreased elevated p-ERK/ERK levels in CFs transfected with miR-21. Conclusion: MiR-21/ERK signalling could be a potential therapeutic pathway for the prevention of myocardial fibrosis. Celastrol ameliorates myocardial fibrosis and cardiac dysfunction, these probably related to miR-21/ERK signaling pathways in vitro and in vivo.