MicroRNA-765 influences arterial stiffness through modulating apelin expression

Yi-Chu Liao; Yung-Song Wang; Edward Hsi; Ming-Hung Chang; Yun-Zhen You; Suh-Hang Hank Juo

doi:10.1016/j.mce.2015.04.006

MicroRNA-765 influences arterial stiffness through modulating apelin expression

Mol Cell Endocrinol. 2015 Aug 15:411:11-9. doi: 10.1016/j.mce.2015.04.006. Epub 2015 Apr 13.

Authors

Yi-Chu Liao¹, Yung-Song Wang², Edward Hsi³, Ming-Hung Chang⁴, Yun-Zhen You⁴, Suh-Hang Hank Juo⁵

Affiliations

¹ 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.
² Institute of Fisheries Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 106, Taiwan.
³ 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.
⁴ Division of Neuromuscular Disease, Neurological Institute, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung 407, Taiwan.
⁵ 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.

PMID: 25882991
DOI: 10.1016/j.mce.2015.04.006

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.

Keywords: Arterial stiffness; Endothelial nitric oxide synthase; MicroRNAs; Single nucleotide polymorphism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Adult
Alleles
Apelin
Female
Genetic Association Studies
Humans
Intercellular Signaling Peptides and Proteins / genetics*
Intercellular Signaling Peptides and Proteins / metabolism
Male
MicroRNAs / genetics*
MicroRNAs / metabolism
Middle Aged
Nitric Oxide Synthase Type III / genetics
Nitric Oxide Synthase Type III / metabolism
Phosphorylation
Polymorphism, Single Nucleotide*
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Sex Factors
Signal Transduction / genetics
Vascular Stiffness / genetics*

Substances

3' Untranslated Regions
APLN protein, human
Apelin
Intercellular Signaling Peptides and Proteins
MIRN765 microRNA, human
MicroRNAs
NOS3 protein, human
Nitric Oxide Synthase Type III
Proto-Oncogene Proteins c-akt