title: Inhibition of miR-200c Restores Endothelial Function in Diabetic Mice Through Suppression of COX-2.
abstract: Endothelial dysfunction plays a crucial role in the development of diabetic vasculopathy. Our initial quantitative PCR results showed an increased miR-200c expression in arteries from diabetic mice and patients with diabetes. However, whether miR-200c is involved in diabetic endothelial dysfunction is unknown. Overexpression of miR-200c impaired endothelium-dependent relaxations (EDRs) in nondiabetic mouse aortas, whereas suppression of miR-200c by anti-miR-200c enhanced EDRs in diabetic db/db mice. miR-200c suppressed ZEB1 expression, and ZEB1 overexpression ameliorated endothelial dysfunction induced by miR-200c or associated with diabetes. More importantly, overexpression of anti-miR-200c or ZEB1 in vivo attenuated miR-200c expression and improved EDRs in db/db mice. Mechanistic study with the use of COX-2(-/-) mice revealed that COX-2 mediated miR-200c-induced endothelial dysfunction and that miR-200c upregulated COX-2 expression in endothelial cells through suppression of ZEB1 and increased production of prostaglandin E2, which also reduced EDR. This study demonstrates for the first time to our knowledge that miR-200c is a new mediator of diabetic endothelial dysfunction and inhibition of miR-200c rescues EDRs in diabetic mice. These new findings suggest the potential usefulness of miR-200c as the target for drug intervention against diabetic vascular complications.
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Huina
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Qu
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jiang-Yun
authors.initials: JY
authors.lastname: Luo
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Lau
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Anatomy, The University of Hong Kong, Hong Kong, China.
authors.forename: George L
authors.initials: GL
authors.lastname: Tipoe
authors.affiliation: Department of Chemistry, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hung Kay
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Chi Fai
authors.initials: CF
authors.lastname: Ng
authors.affiliation: Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ronald Ching Wan
authors.initials: RC
authors.lastname: Ma
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China yu-huang@cuhk.edu.hk.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008875:Middle Aged; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D012077:Renal Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014664:Vasodilation; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; C039919:RNA, recombinant; D000071799:Zinc Finger E-box-Binding Homeobox 1; D012313:RNA; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human