MiR-92a inhibits vascular smooth muscle cell apoptosis: Role of the MKK4-JNK pathway

Lan Zhang, Mi Zhou, Yingjie Wang, Weibin Huang, Gangjian Qin, Neal L. Weintraub, Yaoliang Tang

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Vascular smooth muscle cell (VSMC) apoptosis plays an important role in vascular remodeling and atherosclerotic plaque instability. Oxidative stress in diseased vessels promotes VSMC apoptosis in part by activating the c-Jun N-terminal kinase (JNK) pathway, which has been identified as a molecular target of miR-92a in macrophages. Here, we examined the expression and biological activity of miR-92a in VSMC. Quiescent VSMC exhibited a low basal expression of miR-92a, which was positively regulated by serum stimulation and negatively regulated by H2O2. Overexpression of miR-92a decreased H2O2-induced VSMC apoptosis as indicated by TUNEL assay and cleaved caspase-3 protein levels. Using 3′UTR-reporter assay, we found that miR-92a overexpression led to suppression of both mitogen-activated protein kinase kinase 4 (MKK4)- and JNK1-dependent luciferase activity. We also found that 10 mer seed match between miRNA:mRNA pair is more efficient than 8 mer seed match for us to identify authentic miRNA target. Protein levels of active phospho-JNK and phospho-c-Jun, downstream targets of the MKK4-JNK1 pathway, were also decreased by overexpressing miR-92a in VSMC under oxidative stress. Consistent with these findings, overexpression of MKK4 reversed the anti-apoptotic effects of miR-92a in oxidatively stressed VSMC. In conclusion, miR-92a overexpression inhibits H2O2-induced VSMC apoptosis by directly targeting the MKK4-JNK1 pathway.

Original languageEnglish (US)
Pages (from-to)975-983
Number of pages9
JournalApoptosis
Volume19
Issue number6
DOIs
StatePublished - Jun 2014

Keywords

  • Apoptosis
  • JNK
  • Oxidative stress
  • Vascular smooth muscle cells
  • miR-92a

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

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