title: MicroRNA-765 influences arterial stiffness through modulating apelin expression.
abstract: The present study aims to discover single nucleotide polymorphisms (SNPs) at the apelin gene (APLN) in relation to arterial stiffness, and to explore its molecular mechanisms. A two-step genetic association study was conducted using 799 and 937 subjects in the screening and validation data, respectively. Four tagging SNPs of APLN were tested. SNP rs3115757 was significantly associated with stiffness parameters (β, Ep and PWV) in women, but not in men. The function of rs3115757 was tagged by rs3115758 which is located in miR-765 binding site in the 3' untranslated region of APLN. The reporter assay confirmed that different alleles of rs3115758 interfered with miR-765 binding and then modified APLN expression. Over-expression of miR-765 in endothelial cells decreased mRNA and protein levels of APLN, which further inhibited the phosphorylation of eNOS and ERK/Akt/AMPK signaling. Collectively, our data showed that rs3115758 accounts for the susceptibility of arterial stiffening through miR-765-induced APLN repression.
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Taipei 112, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, No.155, Sec.2, Linong Street, Taipei 112, Taiwan.
authors.forename: Yi-Chu
authors.initials: YC
authors.lastname: Liao
authors.affiliation: Institute of Fisheries Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 106, Taiwan.
authors.forename: Yung-Song
authors.initials: YS
authors.lastname: Wang
authors.affiliation: Department of Genome Medicine, College of Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Road, Kaohsiung 807, Taiwan.
authors.forename: Edward
authors.initials: E
authors.lastname: Hsi
authors.affiliation: Division of Neuromuscular Disease, Neurological Institute, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung 407, Taiwan.
authors.forename: Ming-Hung
authors.initials: MH
authors.lastname: Chang
authors.affiliation: Division of Neuromuscular Disease, Neurological Institute, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung 407, Taiwan.
authors.forename: Yun-Zhen
authors.initials: YZ
authors.lastname: You
authors.affiliation: Department of Genome Medicine, College of Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Road, Kaohsiung 807, Taiwan. Electronic address: hjuo@kmu.edu.tw.
authors.forename: Suh-Hang Hank
authors.initials: SH
authors.lastname: Juo
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000483:Alleles; D000073861:Apelin; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction / Q000235:genetics; D059289:Vascular Stiffness / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C115436:APLN protein, human; D000073861:Apelin; D036341:Intercellular Signaling Peptides and Proteins; C000600151:MIRN765 microRNA, human; D035683:MicroRNAs; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt
keywords: Arterial stiffness; Endothelial nitric oxide synthase; MicroRNAs; Single nucleotide polymorphism