冬凌草甲素可通过促进P21相关的自噬来预防心肌肥大。,Cell Death & Disease

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冬凌草甲素可通过促进P21相关的自噬来预防心肌肥大。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-05-24 , DOI: 10.1038/s41419-019-1617-y
Man Xu _{1,

2,

3} , Chun-Xia Wan _{1,

2,

3} , Si-Hui Huang _{1,

2,

3} , Hui-Bo Wang _{1,

2,

3} , Di Fan _{1,

2,

3} , Hai-Ming Wu _{1,

2,

3} , Qing-Qing Wu _{1,

2,

3} , Zhen-Guo Ma _{1,

2,

3} , Wei Deng _{1,

2,

3} , Qi-Zhu Tang _{1,

2,

3}

Affiliation

自噬是内源性的保护过程。自噬的丧失可能破坏蛋白稳定并增加细胞内氧化应激，这在心脏肥大和心力衰竭的发展中至关重要。Oridonin是一种来自中草药Rabdosia的天然四环素二萜类化合物，具有自噬激活特性。在这项研究中，我们测试了冬凌草甲素是否能预防小鼠和心肌细胞的心肌肥大。我们实施了主动脉束缚术来诱发心脏肥大小鼠模型，并通过管饲法给予了冬凌草甲素4周。用血管紧张素II刺激新生大鼠心肌细胞，以模拟神经体液压力。体内和体外研究均表明，冬凌草甲素可减轻压力超负荷引起的心脏肥大和纤维化，并保留心脏功能。与主动脉束带组相比，接受冬凌草甲素的小鼠表现出增加的抗氧化酶活性并抑制了氧化损伤。此外，冬凌草甲素增强了压力超负荷心脏和血管紧张素II刺激的心肌细胞的心肌自噬。从机理上讲，我们发现冬凌草甲素可调节心肌P21，而胞质P21可通过调节Akt和AMPK磷酸化来激活自噬。这些发现在P21基因敲除小鼠模型中得到了进一步证实。总的来说，压力超负荷引起的自噬功能障碍会导致细胞内蛋白质积聚，从而导致ROS损伤，同时加重心脏肥大。因此，我们的数据表明，冬凌草甲素可促进P21相关的自噬溶酶体降解，从而减轻氧化损伤和心脏肥大。

"点击查看英文标题和摘要"

Oridonin protects against cardiac hypertrophy by promoting P21-related autophagy.

Autophagy is an endogenous protective process; the loss of autophagy could destabilize proteostasis and elevate intracellular oxidative stress, which is critically involved in the development of cardiac hypertrophy and heart failure. Oridonin, a natural tetracycline diterpenoid from the Chinese herb Rabdosia, has autophagy activation properties. In this study, we tested whether oridonin protects against cardiac hypertrophy in mice and cardiomyocytes. We implemented aortic banding to induce a cardiac hypertrophy mouse model, and oridonin was given by gavage for 4 weeks. Neonatal rat cardiomyocytes were stimulated with angiotensin II to simulate neurohumoural stress. Both in vivo and in vitro studies suggested that oridonin treatment mitigated pressure overload-induced cardiac hypertrophy and fibrosis, and also preserved heart function. Mice that received oridonin exhibited increased antioxidase activities and suppressed oxidative injury compared with the aortic banding group. Moreover, oridonin enhanced myocardial autophagy in pressure-overloaded hearts and angiotensin II-stimulated cardiomyocytes. Mechanistically, we discovered that oridonin administration regulated myocardial P21, and cytoplasmic P21 activated autophagy via regulating Akt and AMPK phosphorylation. These findings were further corroborated in a P21 knockout mouse model. Collectively, pressure overload-induced autophagy dysfunction causes intracellular protein accumulation, resulting in ROS injury while aggravating cardiac hypertrophy. Thus, our data show that oridonin promoted P21-related autophagic lysosomal degradation, hence attenuating oxidative injury and cardiac hypertrophy.

更新日期：2019-05-24

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