Dihydroartemisinin ameliorates retinal vascular dysfunction in diabetes mellitus via the FASN/Kmal-mTOR/SREBP1 feedback loop

• DOI: 10.1016/j.phrs.2021.105871
• Publication Date: 2021-10-05T22:22:17Z
• Authors: Chufeng Gu; Xinping She; Chuandi Zhou; Tong Su; Shuai He; Chunren Meng; Qing Gu; Dawei Luo; Zhi Zheng; Qinghua Qiu
• Keywords: Male; Sirolimus; 0301 basic medicine; 0303 health sciences; TOR Serine-Threonine Kinases; Endothelial Cells; Ribosomal Protein S6 Kinases, 70-kDa; Artemisinins; Diabetes Mellitus, Experimental; 3. Good health; Mice, Inbred C57BL; 03 medical and health sciences; Diabetes Mellitus; Animals; Humans; Amino Acid Sequence; Fatty Acid Synthases; Phosphorylation; Sterol Regulatory Element Binding Protein 1; Cell Proliferation; Protein Binding; Signal Transduction

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.