title: MiR-34a contributes to diabetes-related cochlear hair cell apoptosis via SIRT1/HIF-1α signaling.
abstract: Type 2 diabetes (T2DM) has been considered to be associated with a higher likelihood of hearing impairment (HI). However, the molecular mechanisms underlying the association between diabetes and HI are poorly understood. MicroRNAs have recently been demonstrated to be closely associated with hearing loss and considered as promising therapeutic targets. Herein, we investigated whether miR-34a contributes to diabetes-related cochlear hair cell apoptosis and sought to identify the underlying mechanism. The results showed that miR-34a was up-regulated in the cochleas of db/db mice, accompanied by significant hearing threshold elevation and hair cell loss. However, the expression of SIRT1 was significantly down-regulated, while hypoxia-inducible factor-1alpha (HIF-1α) levels were dramatically increased in the cochleas of db/db mice. In addition, in the high-glucose cultured House Ear Institute-Organ of Corti 1 (HEI-OC1) cell line, miR-34a overexpression inhibited sirtuin1 (SIRT1) expression, increased HIF-1α levels and promoted apoptosis. MiR-34a knockdown exerted effects that were diametrically opposed to those observed with overexpression. Interestingly, HIF-1α knockdown almost eliminated the cell apoptosis induced by high glucose levels. We also examined the modulation of HIF-1α expression by SIRT1. The results showed that SIRT1 knockdown further promoted high-glucose-induced HIF-1α expression, while SIRT1 overexpression significantly inhibited HIF-1α level induced by high glucose. These findings point to a new mechanism by which miR-34a exerts its detrimental effects by negatively regulating SIRT1/HIF-1α signaling and provide new therapeutic targets for treating hearing impairment during diabetes.
authors.affiliation: Department of Otolaryngology, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Otolaryngology, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Otolaryngology, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Danfeng
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism Disease, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ming
authors.affiliation: Department of Endocrinology and Metabolism Disease, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism Disease, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology and Metabolism Disease, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Endocrinology and Metabolism Disease, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Endocrinology and Metabolism Disease, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: qiuhxian@163.com.
authors.forename: Qiuhe
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Department of Endocrinology and Metabolism Disease, Xijing Hospital, Forth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: drxingying@hotmail.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xing
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology*; D034381:Hearing Loss / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: HIF-1α; Hearing impairment (HI); SIRT1; T2DM; miR-34a