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MicroRNA-133a regulates DNA methylation in diabetic cardiomyocytes

Vishalakshi Chavali1, Suresh C Tyagi, Paras K Mishra

  • 1Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.

Biochemical and Biophysical Research Communications
|July 31, 2012
PubMed

Insights

MicroRNA-133a (miR-133a) regulates DNA methylation in diabetic hearts. Inhibition of miR-133a increases DNA methyltransferases, while its overexpression mitigates hyperglycemia-induced changes, highlighting its role in diabetic heart disease.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cardiovascular Research

Background:

  • Diabetic cardiomyopathy is a significant complication of diabetes mellitus.
  • Epigenetic modifications, including DNA methylation, play a crucial role in diabetic heart disease.
  • MicroRNAs (miRNAs) are implicated in regulating gene expression and cellular processes, including in the diabetic heart.

Purpose of the Study:

  • To investigate the regulatory role of microRNA-133a (miR-133a) in DNA methylation within the context of diabetic hearts.
  • To determine if miR-133a influences the expression of DNA methyltransferases (DNMTs), specifically DNMT-1, DNMT-3a, and DNMT-3b.

Main Methods:

  • Utilized Ins2(+/-) Akita mice (diabetic model) and C57BL/6J mice (wild-type) alongside HL1 cardiomyocytes.
  • Assessed miR-133a's role using treatments with miR-133a mimics and inhibitors, and varying glucose concentrations (5mM and 25mM).
  • Quantified levels of miR-133a and DNMTs (DNMT-1, -3a, -3b) via multiplex RT-PCR, qPCR, and Western blotting.

Main Results:

  • In Akita mice hearts, miR-133a was downregulated, while DNMT-1 and DNMT-3b were upregulated, suggesting miR-133a inhibition promotes DNA methylation in diabetes.
  • Cardiomyocyte studies showed that miR-133a overexpression inhibited DNMT-1, -3a, and -3b, while silencing miR-133a induced them, confirming miR-133a's regulatory role.
  • High glucose (HG) treatment in cardiomyocytes upregulated DNMT-1 but not DNMT-3a or -3b, indicating acute hyperglycemia primarily affects maintenance methylation.

Conclusions:

  • miR-133a plays a critical role in regulating DNA methylation in the diabetic heart by targeting DNMT enzymes.
  • The observed downregulation of miR-133a in diabetes contributes to increased DNA methyltransferase activity.
  • Overexpression of miR-133a can mitigate hyperglycemia-induced changes in DNA methylation, suggesting therapeutic potential for diabetic heart conditions.

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