Rui Li1, Hanlin Yin1, Juan Wang1, Dongyi He2,3, Qingran Yan4, Liangjing Lu5. 1. Department of Rheumatology, School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University, 145 Shandong Middle Road, Shanghai, 2000001, China. 2. Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, China. hedongyi1967@shutcm.edu.cn. 3. Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200052, China. hedongyi1967@shutcm.edu.cn. 4. Department of Rheumatology, School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University, 145 Shandong Middle Road, Shanghai, 2000001, China. yanqingran@163.com. 5. Department of Rheumatology, School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University, 145 Shandong Middle Road, Shanghai, 2000001, China. lu_liangjing@163.com.
Abstract
OBJECTIVE: The present study was to investigate whether dihydroartemisinin (DHA), which is a highly effective and safe drug in the treatment of malaria, could be repurposed for the treatment of skin fibrosis and vascular dysfunction in systemic sclerosis (SSc). METHODS: The value of DHA was determined using a bleomycin-induced model of skin fibrosis. mRNA transcriptome analysis was performed, and the targets of DHA on fibroblasts were identified. Immunofluorescence staining was used to identify dermal vessels undergoing endothelial-to-mesenchymal transition (EndoMT). Autophagic flux was detected by western blot and mRFP-GFP-LC3 adenovirus vector transfection. RESULTS: Both systemic and topical administration of DHA decreased dermal thickness and collagen deposition and alleviated EndoMT in bleomycin-induced skin fibrosis mice model. Treatment of human umbilical vein endothelial cells (HUVECs) with TGF-β1 resulted in the acquisition of the activation marker (α-SMA) and loss of endothelial markers (CD31 and VE-cadherin), a process that was restored by DHA. DHA significantly suppressed skin fibroblast activation and collagen-1 production mainly through regulating PI3K-Akt pathway. DHA also induced fibroblast autophagic flux and that autophagy dependently suppressed collagen-1 production. CONCLUSION: The results of the present study revealed that oral and topical DHA administration ameliorated tissue fibrosis and protected dermal blood vessels from bleomycin-induced EndoMT. Our study has elucidated the value of repurposing DHA for the treatment of SSc. Key Points • Oral or topical usage of DHA alleviated dermal fibrosis and EndoMT in bleomycin-induced skin fibrosis mice models. • DHA autophagy dependently inhibited fibroblast activation and collagen deposition via PI3K-ATK pathway. • DHA inhibited EndoMT of HUVECs induced by TGF-β1 by the downregulation of α-SMA and the upregulation of CD31 and VE-cadherin.
OBJECTIVE: The present study was to investigate whether dihydroartemisinin (DHA), which is a highly effective and safe drug in the treatment of malaria, could be repurposed for the treatment of skin fibrosis and vascular dysfunction in systemic sclerosis (SSc). METHODS: The value of DHA was determined using a bleomycin-induced model of skin fibrosis. mRNA transcriptome analysis was performed, and the targets of DHA on fibroblasts were identified. Immunofluorescence staining was used to identify dermal vessels undergoing endothelial-to-mesenchymal transition (EndoMT). Autophagic flux was detected by western blot and mRFP-GFP-LC3 adenovirus vector transfection. RESULTS: Both systemic and topical administration of DHA decreased dermal thickness and collagen deposition and alleviated EndoMT in bleomycin-induced skin fibrosismice model. Treatment of human umbilical vein endothelial cells (HUVECs) with TGF-β1 resulted in the acquisition of the activation marker (α-SMA) and loss of endothelial markers (CD31 and VE-cadherin), a process that was restored by DHA. DHA significantly suppressed skin fibroblast activation and collagen-1 production mainly through regulating PI3K-Akt pathway. DHA also induced fibroblast autophagic flux and that autophagy dependently suppressed collagen-1 production. CONCLUSION: The results of the present study revealed that oral and topical DHA administration ameliorated tissue fibrosis and protected dermal blood vessels from bleomycin-induced EndoMT. Our study has elucidated the value of repurposing DHA for the treatment of SSc. Key Points • Oral or topical usage of DHA alleviated dermal fibrosis and EndoMT in bleomycin-induced skin fibrosismice models. • DHA autophagy dependently inhibited fibroblast activation and collagen deposition via PI3K-ATK pathway. • DHA inhibited EndoMT of HUVECs induced by TGF-β1 by the downregulation of α-SMA and the upregulation of CD31 and VE-cadherin.