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AMPKα2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells

Ping Song1, Shuangxi Wang, Chaoyong He

  • 1Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA. psong@ouhsc.edu

Circulation Research
|October 8, 2011
PubMed
Abstract

Insights

Adenosine monophosphate-activated protein kinase alpha 2 (AMPKα2) deletion promotes vascular neointima formation by increasing smooth muscle cell proliferation. This occurs via reduced p27(Kip1) and increased Skp2, leading to neointimal hyperplasia after injury.

Area of Science:

  • Vascular biology and cell signaling.
  • Cardiovascular research.
  • Molecular mechanisms of hyperplasia.

Background:

  • Adenosine monophosphate-activated protein kinase (AMPK) is a key metabolic and redox sensor.
  • AMPK generally suppresses cell proliferation in both normal and cancerous cells.
  • The role of AMPKα in vascular neointima formation following injury remains unclear.

Purpose of the Study:

  • To investigate the specific roles of AMPKα isoforms (AMPKα1 and AMPKα2) in vascular neointima hyperplasia.
  • To elucidate the molecular mechanisms by which AMPKα influences neointima development.
  • To determine if AMPKα affects vascular smooth muscle cell (VSMC) proliferation and arterial remodeling.

Main Methods:

  • Comparative analysis of VSMC proliferation and neointimal hyperplasia in wild-type, AMPKα1(-/-), and AMPKα2(-/-) mice.
  • Assessment of key protein levels including p27(Kip1) and S-phase kinase-associated protein 2 (Skp2).
  • Investigation of the involvement of p52 nuclear factor kappa B (NF-κB)-2 and ubiquitination pathways.
  • Pharmacological and genetic inhibition of AMPK in human VSMCs.

Main Results:

  • AMPKα2 knockout (KO) VSMCs showed significantly increased proliferation compared to wild-type or AMPKα1 KO VSMCs.
  • AMPKα2 deficiency led to decreased p27(Kip1) and increased Skp2 levels, mediated by p52 NF-κB-2 activation.
  • Pharmacological or genetic inhibition of AMPK in human VSMCs mimicked these effects on p27(Kip1) and Skp2.
  • Silencing Skp2 reversed the increased proliferation and normalized p27(Kip1) levels in AMPK-inhibited VSMCs.
  • Neointima formation after wire injury was significantly elevated in AMPKα2(-/-) mice but not in AMPKα1(-/-) mice.

Conclusions:

  • AMPKα2 plays a critical role in suppressing vascular neointima formation.
  • Deletion of AMPKα2 exacerbates neointimal hyperplasia by promoting VSMC proliferation.
  • The mechanism involves p52-Skp2-mediated ubiquitination and degradation of the cyclin-dependent kinase inhibitor p27(Kip1).

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