High cholesterol induces apoptosis and autophagy through the ROS-activated AKT/FOXO1 pathway in tendon-derived stem cells

被引:107
|
作者
Li, Kaiqun [1 ]
Deng, Ye [1 ]
Deng, Ganming [1 ,2 ]
Chen, Pengyu [1 ]
Wang, Yutian [1 ]
Wu, Hangtian [1 ]
Ji, Zhiguo [1 ]
Yao, Zilong [1 ]
Zhang, Xianrong [1 ,3 ]
Yu, Bin [1 ,3 ]
Zhang, Kairui [1 ]
机构
[1] Southern Med Univ, Nanfang Hosp, Dept Orthopaed, 1838 Guangzhou Ave North, Guangzhou 510515, Peoples R China
[2] Baoan Dist Peoples Hosp Shenzhen, Shenzhen 518100, Peoples R China
[3] Southern Med Univ, Nanfang Hosp, Guangdong Prov Key Lab Bone & Cartilage Regenerat, Guangzhou 510515, Peoples R China
基金
中国国家自然科学基金;
关键词
Tendinopathy; Tendon-derived stem cells; Cholesterol; Autophagy; Apoptosis; ROS; AKT; FOXO1; pathway; ROTATOR CUFF; DUAL ROLE; DEATH; LIFE; FATIGUE;
D O I
10.1186/s13287-020-01643-5
中图分类号
Q813 [细胞工程];
学科分类号
摘要
BackgroundHypercholesterolemia increases the risk of tendon pain and tendon rupture. Tendon-derived stem cells (TDSCs) play a vital role in the development of tendinopathy. Our previous research found that high cholesterol inhibits tendon-related gene expression in TDSCs. Whether high cholesterol has other biological effects on TDSCs remains unknown.MethodsTDSCs isolated from female SD rats were exposed to 10mg/dL cholesterol for 24h. Then, cell apoptosis was assessed using flow cytometry and fluorescence microscope. RFP-GFP-LC3 adenovirus transfection was used for measuring autophagy. Signaling transduction was measured by immunofluorescence and immunoblotting. In addition, Achilles tendons from ApoE -/- mice fed with a high-fat diet were histologically assessed using HE staining and immunohistochemistry.ResultsIn this work, we verified that 10mg/dL cholesterol suppressed cell proliferation and migration and induced G0/G1 phase arrest. Additionally, cholesterol induced apoptosis and autophagy simultaneously in TDSCs. Apoptosis induction was related to increased expression of cleaved caspase-3 and BAX and decreased expression of Bcl-xL. The occurrence of autophagic flux and accumulation of LC3-II demonstrated the induction of autophagy by cholesterol. Compared with the effects of cholesterol treatment alone, the autophagy inhibitor 3-methyladenine (3-MA) enhanced apoptosis, while the apoptosis inhibitor Z-VAD-FMK diminished cholesterol-induced autophagy. Moreover, cholesterol triggered reactive oxygen species (ROS) generation and activated the AKT/FOXO1 pathway, while the ROS scavenger NAC blocked cholesterol-induced activation of the AKT/FOXO1 pathway. NAC and the FOXO1 inhibitor AS1842856 rescued the apoptosis and autophagy induced by cholesterol. Finally, high cholesterol elevated the expression of cleaved caspase-3, Bax, LC3-II, and FOXO1 in vivo.ConclusionThe present study indicated that high cholesterol induced apoptosis and autophagy through ROS-activated AKT/FOXO1 signaling in TDSCs, providing new insights into the mechanism of hypercholesterolemia-induced tendinopathy.Graphical abstractHigh cholesterol induces apoptosis and autophagy through the ROS-activated AKT/FOXO1 pathway in tendon-derived stem cells.
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页数:16
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