title: MicroRNA-23a mediates mitochondrial compromise in estrogen deficiency-induced concentric remodeling via targeting PGC-1α.
abstract: It is well known that menopause could worsen age-related ventricular concentric remodeling following estrogen (E2) deficiency. However the underlying mechanisms of such phenomena are not fully understood. Mitochondria, as the 'cellular power station' of hearts, play an important role in maintaining normal cardiac function and structure. Therefore, the present study aims to investigate whether mitochondrial compromise is responsible for E2 deficiency associated concentric remodeling and, if so, what is its underlying molecular mechanism. We found evident concentric remodeling pattern in both postmenopausal and ovariectomized (OVX) mice, which could be attenuated by E2 replacement. Further study showed mitochondrial structural damages and respiratory function impairment in myocardium of both postmenopausal and OVX mice and E2 supplement reversed mitochondrial dysfunction in OVX mice, suggesting that E2 deficiency could induce mitochondrial compromise in the heart. Then, peroxisome proliferator-activated receptor-γ co-activator 1-α (PGC-1α), a key mitochondrial function and biology regulator, was found significantly reduced in both postmenopausal and OVX mice. The reduction of PGC-1α protein level in OVX mice could be rescued by E2 delivery, indicating that E2 could positively regulate PGC-1α expression. Next, we found that microRNA-23a (miR-23a) could be negatively regulated by E2 in both myocardium and cultured cardiomyocytes. Moreover, miR-23a could directly downregulate PGC-1α expression in cardiomyocytes via binding to its 3'UTR which implied that miR-23a could be critical for the downregulation of PGC-1α under E2 deficiency. Overexpression of miR-23a was also found to damage mitochondria in cultured cardiomyocytes, ascribed to PGC-1α downregulation. Taken together, E2 deficiency may cause mitochondrial compromise through miR-23a-mediated PGC-1α downregulation, which may subsequently lead to the menopause-associated concentric remodeling.
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Lu-Yao
authors.initials: LY
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ban
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Si
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang Province 150081, China.
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Zhao
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang Province 150081, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China. Electronic address: a.z.hrbmu@gmail.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province 150081, China. Electronic address: yangbf@ems.hrbmu.edu.cn.
authors.forename: Bao-Feng
authors.initials: BF
authors.lastname: Yang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D019069:Cell Respiration; D015536:Down-Regulation; D004967:Estrogens / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017698:Postmenopause; D014157:Transcription Factors / Q000378:metabolism*; D020257:Ventricular Remodeling
chemical_list: D004967:Estrogens; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors
keywords: Concentric remodeling; E2 deficiency; Mitochondrial; PGC-1α; miR-23a