Angiotensin-II-induced Muscle Wasting is Mediated by 25-Hydroxycholesterol via GSK3 beta Signaling Pathway

作者：Shen, Congcong; Zhou, Jin^*; Wang, Xiaoxiao; Yu, Xi-Yong; Liang, Chun; Liu, Bin; Pan, Xiangbin; Zhao, Qiong; Song, Jenny Lee; Wang, Jiajun; Bao, Meiyu; Wu, Chaofan; Li, Yangxin^*; Song, Yao-Hua^*

来源：EBioMedicine, 2017, 16: 238-250.

DOI：10.1016/j.ebiom.2017.01.040

• Cardiac cachexia
• Heart failure
• TNF-alpha
• Angiotensin II
• Ch25h

While angiotensin II (ang II) has been implicated in the pathogenesis of cardiac cachexia (CC), the molecules that mediate ang II's wasting effect have not been identified. It is known TNF-alpha level is increased in patients with CC, and TNF-alpha release is triggered by ang II. We therefore hypothesized that ang II induced muscle wasting is mediated by TNF-alpha. Ang II infusion led to skeletal muscle wasting in wild type (WT) but not in TNF alpha type 1 receptor knockout (TNFR1KO) mice, suggesting that ang II induced muscle loss is mediated by TNF-alpha through its type 1 receptor. Microarray analysis identified cholesterol 25-hydroxylase (Ch25h) as the down stream target of TNF-alpha. Intraperitoneal injection of 25-hydroxycholesterol (25-OHC), the product of Ch25h, resulted inmuscle loss in C57BL/6 mice, accompanied by increased expression of atrogin-1, MuRF1 and suppression of IGF-1/Akt signaling pathway. The identification of 25-OHC as an inducer of muscle wasting has implications for the development of specific treatment strategies in preventing muscle loss.

• 出版日期2017-2
• 单位广东省心血管病研究所; 广州医科大学; 中国人民解放军第二军医大学; 天津市中医药研究院附属医院; 中国医学科学院阜外医院; 苏州大学; 南京医科大学; 吉林大学