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Heart Vessels. 2017 Dec;32(12):1523-1535. doi: 10.1007/s00380-017-1054-8. Epub 2017 Sep 30.

Interleukin-6 downregulated vascular smooth muscle cell contractile proteins via ATG4B-mediated autophagy in thoracic aortic dissection.

Author information

1
Department of Cardiovascular Surgery, Changhai Hospital, Second Military Medical University, 168 Changhai Rd, Shanghai, 200433, China.
2
Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
3
Department of Cardiovascular Surgery, Changhai Hospital, Second Military Medical University, 168 Changhai Rd, Shanghai, 200433, China. lufanglin1@yeah.net.
4
Department of Cardiovascular Surgery, Changhai Hospital, Second Military Medical University, 168 Changhai Rd, Shanghai, 200433, China. zhiyunxu@yeah.net.

Abstract

Interleukin-6 (IL-6) overexpression played an important role in the pathogenesis of thoracic aortic dissection (TAD). Our previous study found enhanced autophagy accompanying with contractile proteins α smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α) degradation in TAD aortic vascular smooth muscle cells (VSMCs). Autophagy is an important way for intracellular proteins degradation, while IL-6 has been found as a contributing factor of autophagy in some cancers. These indicated IL-6 might contribute to the occurrence of TAD by promoting autophagy-induced contractile proteins degradation, which has not been investigated. The aim of the present study is to verify this hypothesis and investigate the mechanism of it. We collected 10 TAD and 10 control aortic specimens from patients underwent TAD surgical repair and coronary artery bypass grafting, respectively. Quantitative real-time polymerase chain reaction was used to detect mRNA expression. Protein expression level was assessed by enzyme-linked immunosorbent assay, western blot, and immunohistochemistry. Microtubule-associated protein 1 light chain 3 beta overexpression adenovirus with green and red fluorescent protein tags and transmission electron microscopy were used to detect autophagy level in VSMCs. 3-Methyladenine (3-MA) and chloroquine were used to block autophagy in human VSMCs. Experiment results showed that the expression of IL-6 was significantly increased accompanying with up-regulated autophagy in TAD aortic wall compared with controls. In vitro results showed that IL-6 stimulation decreased the expression of VSMCs contractile proteins α-SMA and SM22α accompanying with up-regulated autophagy. Blocking autophagy with 3-MA or chloroquine inhibited IL-6 induced α-SMA and SM22α degradation. Further investigation showed that autophagy-related 4B cysteine peptidase (ATG4B) was significantly overexpressed in TAD aortic wall and played important role in IL-6 induced autophagy up-regulation. ATG4B knockdown blocked IL-6-induced autophagy and α-SMA and SM22α degradation, while ATG4B overexpression partly replaced the function of IL-6 in human VSMCs. In conclusion, our study demonstrated that IL-6 downregulated expression of VSMCs contractile proteins α-SMA and SM22α via enhancing ATG4B-mediated autophagy in TAD.

KEYWORDS:

ATG4B; Autophagy; Interleukin-6; Smooth muscle cell; Thoracic aortic dissection

PMID:
28965202
DOI:
10.1007/s00380-017-1054-8
[Indexed for MEDLINE]

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