title: Lovastatin upregulates microRNA-29b to reduce oxidative stress in rats with multiple cardiovascular risk factors.
abstract: OBJECTIVE
  Proteasome-linked oxidative stress is believed to cause endothelial dysfunction, an early event in cardiovascular diseases (CVD). Statin, as HMG-CoA reductase inhibitor, prevents endothelial dysfunction in CVD. However, the molecular mechanism of statin-mediated normalization of endothelial function is not completely elucidated.
  
  
  RESULTS
  Lovastatin time/dose-dependently increased miR-29b expression and decreased proteasome activity in cultured human umbilical vein endothelial cells (HUVECs). Anti-miR-29b or overexpression of PA200 abolished lovastatin-induced inhibition of proteasome activity in HUVECs. In contrast, pre-miR-29b or PA200 siRNA mimics these effects of lovastatin on proteasome activity. Lovastatin inhibited oxidative stress induced by multiple oxidants including ox-LDL, H2O2, TNFα, homocysteine thiolactone (HTL), and high glucose (HG), which were reversed by inhibition of miR-29b in HUVECs. Ex vivo analysis indicated that lovastatin normalized the acetylcholine-induced endothelium-dependent relaxation and the redox status in isolated rat aortic arteries exposure to multiple cardiovascular risk factors. In vivo analysis revealed that administration of lovastatin remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats with hyperglycemia, dyslipidemia, and hyperhomocysteinemia, as well as increased miR-29b expressions, reduced PA200 protein levels, and suppression of proteasome activity in aortic tissues.
  
  
  CONCLUSIONS
  Upregulation of miR-29b expression is a common mechanism contributing to endothelial dysfunction induced by multiple cardiovascular risk factors through PA200-dependent proteasome-mediated oxidative stress, which is prevented by lovastatin.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
authors.forename: Fu
authors.initials: F
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ma
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Liang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
authors.forename: Xue-Qing
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
authors.forename: Mei-Rong
authors.initials: MR
authors.lastname: Shan
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Rehabilitation Medicine, Jinan Municipal Hospital of Traditional Chinese Medicine, Jinan, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jia
authors.affiliation: Department of Pharmacology, College of Pharmacy, Xinxiang Medical University, Xinxiang, China.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Yin
authors.affiliation: Department of Pharmacology, Pharmaceutical College, Central South University, Changsha, China.
authors.forename: Xue-Ying
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Biology and Chemistry, Denison University, Granville, OH, USA.
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, China.
authors.forename: Qi-Sheng
authors.initials: QS
authors.lastname: Peng
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
authors.forename: Yu-Guo
authors.initials: YG
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Pharmaceutical College, Central South University, Changsha, China.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, College of Pharmacy, Xinxiang Medical University, Xinxiang, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, Jinan, China.
authors.forename: Shuang-Xi
authors.initials: SX
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020138:Hyperhomocysteinemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008148:Lovastatin / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects
chemical_list: D055372:AMP-Activated Protein Kinases; D000975:Antioxidants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D035683:MicroRNAs; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; C526366:MIRN29 microRNA, rat; C532045:MIRN29a microRNA, human; C521188:PSME4 protein, human
keywords: PA200; Pathology Section; endothelial dysfunction; lovastatin; microRNA-29b; oxidative stress