title: Inhibition of Aberrant MicroRNA-133a Expression in Endothelial Cells by Statin Prevents Endothelial Dysfunction by Targeting GTP Cyclohydrolase 1 in Vivo.
abstract: BACKGROUND
  GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase uncoupling in endothelial dysfunction. MicroRNAs (miRs) are a class of regulatory RNAs that negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation.
  
  
  METHODS
  Endothelial function was assessed by measuring acetylcholine-induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by quantitative reverse transcription polymerase chain reaction and fluorescence in situ hybridization.
  
  
  RESULTS
  We first demonstrated that GCH1 mRNA is a target of miR-133a. In endothelial cells, miR-133a was robustly induced by cytokines/oxidants and inhibited by lovastatin. Furthermore, lovastatin upregulated GCH1 and tetrahydrobiopterin, and recoupled endothelial nitric oxide synthase in stressed endothelial cells. These actions of lovastatin were abolished by enforced miR-133a expression and were mirrored by a miR-133a antagomir. In mice, hyperlipidemia- or hyperglycemia-induced ectopic miR-133a expression in the vascular endothelium, reduced GCH1 protein and tetrahydrobiopterin levels, and impaired endothelial function, which were reversed by lovastatin or miR-133a antagomir. These beneficial effects of lovastatin in mice were abrogated by in vivo miR-133a overexpression or GCH1 knockdown. In rats, multiple cardiovascular risk factors including hyperglycemia, dyslipidemia, and hyperhomocysteinemia resulted in increased miR-133a vascular expression, reduced GCH1 expression, uncoupled endothelial nitric oxide synthase function, and induced endothelial dysfunction, which were prevented by lovastatin.
  
  
  CONCLUSIONS
  Statin inhibits aberrant miR-133a expression in the vascular endothelium to prevent endothelial dysfunction by targeting GCH1. Therefore, miR-133a represents an important therapeutic target for preventing cardiovascular diseases.
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Yin
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Xue-Ying
authors.initials: XY
authors.lastname: Sun
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Hui
authors.initials: H
authors.lastname: Ma
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Mo-Li
authors.initials: ML
authors.lastname: Zhu
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Fan-Rong
authors.initials: FR
authors.lastname: Zhao
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Guang-Rui
authors.initials: GR
authors.lastname: Wan
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Fan
authors.initials: F
authors.lastname: Jiang
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Qi-Sheng
authors.initials: QS
authors.lastname: Peng
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.).
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Liu
authors.affiliation: From School of Pharmacy and School of Basic Medical Sciences, Xinxiang Medical University, China (P.L., Y.-L.Y., M.-L.Z., F.-R.Z., P.X., G.-R.W., S.-X.W.); The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China (T.G., H.M., Y.C., F.J., S.-X.W.); Department of Pharmacology, School of Pharmacy, Central South University, Changsha, China (X.-Y.S., L.-Y.L.); The Key Laboratory for Zoonosis Research, Institute of Zoonosis, Jilin University, Changchun, China (Q.-S.P.); and Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China (C.L.). shuangxiwang@sdu.edu.cn.
authors.forename: Shuang-Xi
authors.initials: SX
authors.lastname: Wang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006136:GTP Cyclohydrolase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012307:Risk Factors; D015854:Up-Regulation
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C549446:MIRN133 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; D009569:Nitric Oxide; D008148:Lovastatin; D052250:Nitric Oxide Synthase Type III; D006136:GTP Cyclohydrolase; C000597358:Gch1 protein, mouse
keywords: GTP cyclohydrolase; MIRN133; endothelial cells; hydroxymethylglutaryl-CoA reductase inhibitors; mic; nitric oxide synthase; roRNA, rat; type III