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Aberration methylation of miR-34b was involved in regulating vascular calcification by targeting Notch1

Xiao Lin1,2, Fuxingzi Li1, Feng Xu1

  • 1Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China.

Aging
|May 27, 2019
PubMed

Insights

MicroRNA-34b (miR-34b) plays a key role in preventing vascular calcification in patients with end-stage renal disease. Its regulation by DNA methylation and Notch1 offers a potential new therapeutic target for this condition.

Area of Science:

  • Molecular Biology
  • Renal Disease Pathophysiology
  • Cardiovascular Research

Background:

  • Vascular calcification is a major contributor to mortality in end-stage renal disease (ESRD) patients.
  • The molecular mechanisms underlying vascular calcification require further elucidation for therapeutic development.

Purpose of the Study:

  • To investigate the role and underlying mechanisms of microRNA-34b (miR-34b) in vascular smooth muscle cell (VSMC) calcification.
  • To explore the potential of targeting miR-34b for therapeutic intervention in vascular calcification.

Main Methods:

  • Assessed miR-34b expression in VSMCs treated with high inorganic phosphate (Pi), mouse models (5/6 nephrectomy with high-Pi diet), and human renal arteries from uraemia patients.
  • Utilized miR-34b overexpression and inhibition to study its effect on VSMC calcification.
  • Investigated DNA methylation of miR-34b using bisulphite sequencing PCR (BSP) and the role of DNA methyltransferase 3a (DNMT3a) and 5-aza-2'-deoxycytidine (5-aza).
  • Validated Notch1 as a downstream target of miR-34b.

Main Results:

  • miR-34b expression was significantly suppressed in calcified VSMCs, arteries from 5/6 NTP mice, and uraemic human renal arteries.
  • Overexpression of miR-34b inhibited VSMC calcification, while inhibition of miR-34b enhanced it.
  • Hypermethylation of CpG sites upstream of miR-34b DNA, mediated by increased DNMT3a, was observed in calcified tissues.
  • DNMT3a knockdown abrogated the effect of high Pi on VSMC calcification, and 5-aza restored miR-34b expression.
  • Notch1 was identified as a functional target of miR-34b involved in VSMC calcification.

Conclusions:

  • miR-34b plays a critical role in regulating VSMC calcification both in vitro and in vivo.
  • miR-34b's function is modulated by upstream DNA methylation (via DNMT3a) and downstream target gene expression (Notch1).
  • Modulation of miR-34b presents a promising novel therapeutic strategy for vascular calcification in ESRD.

Keywords:
Notch1methylationmiR-34bvascular calcificationvascular smooth muscle cells

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