Activation of AKT by O-linked N-Acetylglucosamine induces vascular calcification in diabetes mellitus

Jack M. Heath, Yong Sun, Kaiyu Yuan, Wayne E. Bradley, Silvio Litovsky, Louis J. Dell'Italia, John C. Chatham, Hui Wu, Yabing Chen

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

RATIONALE:: Vascular calcification is a serious cardiovascular complication that contributes to the increased morbidity and mortality of patients with diabetes mellitus. Hyperglycemia, a hallmark of diabetes mellitus, is associated with increased vascular calcification and increased modification of proteins by O-linked N-acetylglucosamine (O-GlcNAcylation). OBJECTIVE:: We sought to determine the role of protein O-GlcNAcylation in regulating vascular calcification and the underlying mechanisms. METHODS AND RESULTS:: Low-dose streptozotocin-induced diabetic mice exhibited increased aortic O-GlcNAcylation and vascular calcification, which was also associated with impaired aortic compliance in mice. Elevation of O-GlcNAcylation by administration of Thiamet-G, a potent inhibitor for O-GlcNAcase that removes O-GlcNAcylation, further accelerated vascular calcification and worsened aortic compliance of diabetic mice in vivo. Increased O-GlcNAcylation, either by Thiamet-G or O-GlcNAcase knockdown, promoted calcification of primary mouse vascular smooth muscle cells. Increased O-GlcNAcylation in diabetic arteries or in the O-GlcNAcase knockdown vascular smooth muscle cell upregulated expression of the osteogenic transcription factor Runx2 and enhanced activation of AKT. O-GlcNAcylation of AKT at two new sites, T430 and T479, promoted AKT phosphorylation, which in turn enhanced vascular smooth muscle cell calcification. Site-directed mutation of AKT at T430 and T479 decreased O-GlcNAcylation, inhibited phosphorylation of AKT at S473 and binding of mammalian target of rapamycin complex 2 to AKT, and subsequently blocked Runx2 transactivity and vascular smooth muscle cell calcification. CONCLUSIONS:: O-GlcNAcylation of AKT at 2 new sites enhanced AKT phosphorylation and activation, thus promoting vascular calcification. Our studies have identified a novel causative effect of O-GlcNAcylation in regulating vascular calcification in diabetes mellitus and uncovered a key molecular mechanism underlying O-GlcNAcylation-mediated activation of AKT.

Original languageEnglish (US)
Pages (from-to)1094-1102
Number of pages9
JournalCirculation research
Volume114
Issue number7
DOIs
StatePublished - Mar 28 2014
Externally publishedYes

Keywords

  • diabetes mellitus
  • myocytes, smooth muscle
  • vascular calcification

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Activation of AKT by O-linked N-Acetylglucosamine induces vascular calcification in diabetes mellitus'. Together they form a unique fingerprint.

Cite this