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

Abstract

RATIONALE:

Adenosine monophosphate-activated protein kinase (AMPK), a metabolic and redox sensor, is reported to suppress cell proliferation of nonmalignant and tumor cells. Whether AMPKα alters vascular neointima formation induced by vascular injury is unknown.

OBJECTIVE:

The aim of this study was to determine the roles of AMPKα in the development of vascular neointima hyperplasia and to elucidate the underlying mechanisms.

METHODS AND RESULTS:

Vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia were evaluated in cultured VSMCs and wire-injured mouse carotid arteries from wild-type (WT, C57BL/6J), AMPKα2(-/-), and AMPKα1(-/-) mice. Mouse VSMCs derived from aortas of AMPKα2(-/-) mice exhibited increased proliferation compared with either WT or AMPKα1(-/-) VSMCs. Further, deletion of AMPKα2 but not AMPKα1 reduced the level of p27(Kip1), a cyclin-dependent kinase inhibitor, and increased the level of S-phase kinase-associated protein 2 (Skp2), a known E3 ubiquitin ligase for p27(Kip1), through activation of p52 nuclear factor kappa B (NF-κB)-2. Moreover, either pharmacological (ie, through compound C) or genetical (ie, through AMPKα2-specific siRNA) inhibition of AMPK decreased p27(Kip1) levels but increased the abundance of Skp2 in human VSMCs. Furthermore, gene silencing of Skp2 reversed the levels of p27(Kip1) and VSMCs proliferation. Finally, neointima formation after mechanical arterial injury was increased in AMPKα2(-/-) but not AMPKα1(-/-) mice.

CONCLUSIONS:

These findings indicate that deletion of AMPKα2 through p52-Skp2-mediated ubiquitination and degradation of p27(Kip1) accentuates neointimal hyperplasia in response to wire injury.

• Authors: Ping Song, Shuangxi Wang, Chaoyong He, Shaobin Wang, Bin Liang, Benoit Viollet, Ming-Hui Zou
• Journal: Circulation research (Circ Res) Vol. 109 Issue 11 Pg. 1230-9 (11 11 2011) ISSN: 1524-4571 [Electronic] United States
• PMID: 21980125 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• RNA, Small Interfering
• S-Phase Kinase-Associated Proteins
• Cyclin-Dependent Kinase Inhibitor p27
• AMPK alpha1 subunit, mouse
• AMPK alpha2 subunit, mouse
• AMP-Activated Protein Kinases
• Proteasome Endopeptidase Complex

Topics

• AMP-Activated Protein Kinases (deficiency, genetics, physiology)
• Animals
• Carotid Artery Injuries (enzymology, pathology)
• Cell Division
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Gene Deletion
• Hyperplasia
• Mice
• Mice, Knockout
• Muscle, Smooth, Vascular (pathology)
• Myocytes, Smooth Muscle (enzymology)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Processing, Post-Translational
• RNA Interference
• RNA, Small Interfering (pharmacology)
• S-Phase Kinase-Associated Proteins (biosynthesis, genetics, physiology)
• Tunica Intima (enzymology, injuries, pathology)
• Ubiquitination
• Up-Regulation