Cyclic helix B peptide promotes random‐pattern skin flap survival via TFE3‐mediated enhancement of autophagy and reduction of ROS levels. (14th December 2021)

• Record Type: Journal Article
• Authors: Lou, Junsheng; Zhang, Haojie; Qi, Jianjun; Xu, Yu; Wang, Xingyu; Jiang, Jingtao; Hu, Xinli; Ni, Libin; Cai, Yuepiao; Wang, Xiangyang; Gao, Weiyang; Xiao, Jian; Zhou, Kailiang
• Is Part Of: British journal of pharmacology. Volume 179:Number 2(2022)
• Page Start: 301
• Page End: 321
• Publication Date: 2021-12-14
• Subjects: autophagy -- CHBP -- oxidative stress -- random skin flaps -- TFE3; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.15702
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : Background and Purpose: Necrosis of random‐pattern skin flaps limits their clinical application. Helix B surface peptide (HBSP) protects tissues from ischaemia–reperfusion injury but its short plasma half‐life limits its applications. Here, we have synthesized cyclic helix B peptide (CHBP) and investigated its role in flap survival and the underlying mechanisms. Experimental Approach: Flap viability was evaluated by survival area analysis, laser Doppler blood flow and histological analysis. RNA sequencing was used to identify mechanisms underlying the effects of CHBP. Levels of autophagy, oxidative stress, pyroptosis, necroptosis and molecules related to the AMP‐activated protein kinase (AMPK)–TRPML1–calcineurin signalling pathway were assayed with Western blotting, RT‐qPCR, immunohistochemistry and immunofluorescence. Key Results: The results indicated that CHBP promoted the survival of random‐pattern skin flaps. The results of RNA sequencing analysis indicated that autophagy, oxidative stress, pyroptosis and necroptosis were involved in the ability of CHBP to promote skin flap survival. Restoration of autophagy flux and enhanced resistance to oxidative stress contributed to inhibition of pyroptosis and necroptosis. Increased autophagy and inhibition of oxidative stress in the ischaemic flaps were regulated by transcription factor E3 (TFE3). A decrease in the levels of TFE3 caused a reduction in autophagy flux and accumulation of ROS and eliminated the protective effect of CHBP. Moreover, CHBP regulated the activity of TFE3 via the AMPK–TRPML1–calcineurin signalling pathway. Conclusion and Implications: CHBP promotes skin flap survival by up‐regulating autophagy and inhibiting oxidative stress in the ischaemic flap and may have potential clinical applications. Abstract : CHBP inhibits ischaemic necrosis in the distal end of random‐pattern skin flaps. CHBP promotes autophagy and inhibits oxidative stress to inhibit pyroptosis and necroptosis in ischaemic skin flaps. In ischaemic flap, CHBP‐mediated enhancement of autophagy contributes to the suppression of ROS. The effect of CHBP on autophagy and oxidative stress is mediated by TFE3 in ischaemic flaps. CHBP regulates TFE3 via the AMPK–TRPML1–calcineurin signalling pathway in ischaemic flaps.