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EBioMedicine. 2017 Feb;16:238-250. doi: 10.1016/j.ebiom.2017.01.040. Epub 2017 Jan 30.

Angiotensin-II-induced Muscle Wasting is Mediated by 25-Hydroxycholesterol via GSK3β Signaling Pathway.

Author information

1
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China.
2
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, PR China. Electronic address: 13913506369@163.com.
3
Guangdong Cardiovascular Institute, Guangzhou Medical University, Guangzhou, Guangdong, PR China.
4
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415, Fengyang Road, Shanghai, PR China.
5
Cardiovascular Disease Center, The First Hospital of Ji Lin University, Changchun, Jilin 130021, PR China.
6
Department of Cardiac Surgery, Fuwai Hospital, PR China.
7
Department of Gynecology, The Affiliated Maternity and Child Health Hospital of Nanjing Medical University, Wuxi, PR China.
8
The Department of Cardiovascular Surgery of the First Affiliated Hospital and the Institute for Cardiovascular Science, Soochow University, Suzhou, Jiangsu 215123, PR China. Electronic address: yangxin_li@yahoo.com.
9
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PR China. Electronic address: yaohua_song1@yahoo.com.

Abstract

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-α level is increased in patients with CC, and TNF-α release is triggered by ang II. We therefore hypothesized that ang II induced muscle wasting is mediated by TNF-α. 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-α through its type 1 receptor. Microarray analysis identified cholesterol 25-hydroxylase (Ch25h) as the down stream target of TNF-α. Intraperitoneal injection of 25-hydroxycholesterol (25-OHC), the product of Ch25h, resulted in muscle 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.

KEYWORDS:

Angiotensin II; Cardiac cachexia; Ch25h; Heart failure; TNF-α

PMID:
28161398
PMCID:
PMC5474518
DOI:
10.1016/j.ebiom.2017.01.040
[Indexed for MEDLINE]
Free PMC Article

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