PMID- 34619345 OWN - NLM STAT- MEDLINE DCOM- 20220214 LR - 20240226 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 174 DP - 2021 Dec TI - Dihydroartemisinin ameliorates retinal vascular dysfunction in diabetes mellitus via the FASN/Kmal-mTOR/SREBP1 feedback loop. PG - 105871 LID - S1043-6618(21)00455-2 [pii] LID - 10.1016/j.phrs.2021.105871 [doi] AB - Microvascular dysfunction is the primary aetiology of visual impairment caused by diabetic retinopathy (DR). Dihydroartemisinin (DHA), the active metabolite of the antimalarials artemisinins, exhibits antiangiogenic properties in numerous diseases. Here, we investigated the function and mechanisms of DHA as a vasculoprotective agent in DR. DHA exerted its protective effect on vascular injuries in diabetic mice and inhibited cell proliferation and tube formation in human retinal microvascular endothelial cells by decreasing the level of fatty acid synthase (FASN), enhancing the malonylation of mechanistic target of rapamycin (mTOR) at lysine 1218 (K1218) and attenuating the activation of mTOR complex 1 (mTORC1). Impressively, a chemosynthetic small interfering RNA against FASN and mutagenesis of K1218 of mTOR showed therapeutic potential in suppressing cell proliferation and tube formation induced by high glucose. Notably, suppression of mTORC1 kinase activity further inhibited FASN by reducing p70S6K phosphorylation to subsequently reduce the expression of sterol regulatory element binding protein 1, which interacted directly with the FASN promoter at nucleotide positions -64 and -55. In conclusion, our study elucidated the promising effects of FASN and malonylation on vascular injuries of DR and indicated the great potential of DHA as a therapeutic approach. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Gu, Chufeng AU - Gu C AD - Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China. FAU - She, Xinping AU - She X AD - Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China. FAU - Zhou, Chuandi AU - Zhou C AD - Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China. FAU - Su, Tong AU - Su T AD - Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China. FAU - He, Shuai AU - He S AD - Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China. FAU - Meng, Chunren AU - Meng C AD - Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China. FAU - Gu, Qing AU - Gu Q AD - Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China. FAU - Luo, Dawei AU - Luo D AD - Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China. FAU - Zheng, Zhi AU - Zheng Z AD - Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China. Electronic address: zzheng88@sjtu.edu.cn. FAU - Qiu, Qinghua AU - Qiu Q AD - Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China; Department of Ophthalmology, Shigatse People's Hospital, Shigatse, Xizang, PR China. Electronic address: qinghuaqiu@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211005 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Artemisinins) RN - 0 (Sterol Regulatory Element Binding Protein 1) RN - EC 2.3.1.85 (Fatty Acid Synthases) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM EIN - Pharmacol Res. 2022 Sep;183:106410. PMID: 35999108 MH - Amino Acid Sequence MH - Animals MH - Artemisinins/*pharmacology MH - Cell Proliferation/drug effects MH - Diabetes Mellitus/*drug therapy MH - Diabetes Mellitus, Experimental MH - Endothelial Cells MH - Fatty Acid Synthases/*metabolism MH - Humans MH - Male MH - Mice, Inbred C57BL MH - Phosphorylation MH - Protein Binding MH - Ribosomal Protein S6 Kinases, 70-kDa/metabolism MH - Signal Transduction MH - Sirolimus/metabolism MH - Sterol Regulatory Element Binding Protein 1/genetics/*metabolism MH - TOR Serine-Threonine Kinases/*metabolism MH - Mice OTO - NOTNLM OT - Diabetic retinopathy OT - Dihydroartemisinin OT - Dihydroartemisinin (PubChem CID: 3000518) OT - Fatty acid synthase OT - Mechanistic target of rapamycin OT - Posttranslational modifications OT - Vascular dysfunction EDAT- 2021/10/08 06:00 MHDA- 2022/02/15 06:00 CRDT- 2021/10/07 20:18 PHST- 2021/03/30 00:00 [received] PHST- 2021/08/21 00:00 [revised] PHST- 2021/09/02 00:00 [accepted] PHST- 2021/10/08 06:00 [pubmed] PHST- 2022/02/15 06:00 [medline] PHST- 2021/10/07 20:18 [entrez] AID - S1043-6618(21)00455-2 [pii] AID - 10.1016/j.phrs.2021.105871 [doi] PST - ppublish SO - Pharmacol Res. 2021 Dec;174:105871. doi: 10.1016/j.phrs.2021.105871. Epub 2021 Oct 5.