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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
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Apolipoprotein E-mediated cell cycle arrest linked to p27 and the Cox2-dependent repression of miR221/222

Devashish Kothapalli1, Paola Castagnino, Daniel J Rader

  • 1Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.

Atherosclerosis
|January 9, 2013
PubMed
Abstract

Insights

Apolipoprotein E3 (apoE3) inhibits vascular smooth muscle cell proliferation by downregulating miR221/222, leading to increased p27 expression. This mechanism enhances cardiovascular protection by controlling cell cycle regulation.

Area of Science:

  • Cardiovascular Biology
  • Molecular Biology
  • Cell Biology

Background:

  • Apolipoprotein E (apoE) exerts lipid-independent cardiovascular protective effects.
  • One such effect is the inhibition of vascular smooth muscle cell (VSMC) proliferation.
  • The precise cell cycle regulatory mechanisms underlying apoE's anti-mitogenic action require elucidation.

Purpose of the Study:

  • To identify and characterize the cell cycle regulatory mechanisms responsible for apoE's anti-mitogenic effect on VSMCs.
  • To investigate the role of microRNAs in apoE-mediated cell cycle control.

Main Methods:

  • Primary VSMCs were stimulated with serum in the presence or absence of apoE3.
  • Expression levels of p27(kip1), Cox2, PGI(2)-IP signaling, and miR221/222 were analyzed.
  • miR222 expression was reconstituted to assess its impact on p27 and S phase entry.
  • Experiments were conducted in vitro and in vivo using apoE3-null mice.

Main Results:

  • ApoE3 upregulated the cyclin-dependent kinase inhibitor p27(kip1) in VSMCs via Cox2 and PGI(2)-IP signaling.
  • ApoE3 inhibited the expression of miR221/222, which post-translationally regulate p27.
  • Reconstitution of miR222 expression reversed the effects of apoE3 on p27 and S phase entry.
  • ApoE3-containing HDL, but not LDL or apoA-1, repressed miR221/222 expression.
  • Regulation of miR221/222 by apoE isoforms was independent of the C-terminal lipid-binding domain.
  • miR221/222 levels were elevated in apoE3-null mice and reduced upon apoE3 reconstitution.

Conclusions:

  • Apolipoprotein E inhibits VSMC proliferation by modulating p27 expression through the regulation of miR221/222.
  • This microRNA-dependent pathway represents a novel mechanism contributing to the cardiovascular protective effects of apoE and apoE-HDL.

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