title: Knockdown of microRNA-195 contributes to protein phosphatase-2A inactivation in rats with chronic brain hypoperfusion.
abstract: Reduction of protein phosphatase-2A (PP2A) activity is a common clinical feature of Alzheimer's disease and vascular dementia. In this study, we observed that chronic brain hypoperfusion induced by bilateral common carotid artery occlusion of rats led to PP2A inactivation based on the increase in tyrosine-307 phosphorylation and leucine-309 demethylation of PP2AC and the depression in PP2ABα. Knockdown of miR-195 using overexpression of its antisense molecule oligonucleotide (pre-AMO-miR-195) delivered by a lentivirus (lenti-pre-AMO-miR-195) increased tyrosine-307 phosphorylation and decreased both PP2ABα expression and leucine-309 methylation; these effects were prevented by the overexpression of miR-195 using lenti-pre-miR-195 and controlled by an increase in methylesterase (PME-1) and a decrease in leucine carboxyl methyltransferase-1. In vitro studies demonstrated that miR-195 regulated PME-1 expression by binding to the Ppme1 gene 3'-untranslated region (3'UTR) domain. Masking the miR-195 binding sites in the amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 genes prevented miR-195-induced leucine carboxyl methyltransferase-1 elevation. We concluded that the miR-195 downregulation in chronic brain hypoperfusion involved PP2A inactivity, which was mediated by the post-transcriptional regulation PME-1, APP, and β-site APP cleaving enzyme 1 expression.
authors.affiliation: Department of Pharmacology, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Cheng-Di
authors.initials: CD
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: De-Kang
authors.initials: DK
authors.lastname: Zong
authors.affiliation: Department of Pharmacology, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Shuang-Chao
authors.initials: SC
authors.lastname: Pei
authors.affiliation: Department of Pharmacology, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: Hao
authors.affiliation: Department of Pharmacology, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Xing
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China; Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China. Electronic address: azhrbmu@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002908:Chronic Disease; D015536:Down-Regulation; D004789:Enzyme Activation / Q000235:genetics*; D055785:Gene Knockdown Techniques; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D011497:Protein O-Methyltransferase / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: C584139:MIRN195 microRNA, rat; D035683:MicroRNAs; C524761:LCMT1 protein, human; D011497:Protein O-Methyltransferase; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; D054648:Protein Phosphatase 2
keywords: Chronic brain hypoperfusion; LCMT-1; PME-1; PP2A; miR-195