AKT2 confers protection against aortic aneurysms and dissections

Circ Res. 2013 Feb 15;112(4):618-32. doi: 10.1161/CIRCRESAHA.112.300735. Epub 2012 Dec 18.

Abstract

Rationale: Aortic aneurysm and dissection (AAD) are major diseases of the adult aorta caused by progressive medial degeneration of the aortic wall. Although the overproduction of destructive factors promotes tissue damage and disease progression, the role of protective pathways is unknown.

Objective: In this study, we examined the role of AKT2 in protecting the aorta from developing AAD.

Methods and results: AKT2 and phospho-AKT levels were significantly downregulated in human thoracic AAD tissues, especially within the degenerative medial layer. Akt2-deficient mice showed abnormal elastic fibers and reduced medial thickness in the aortic wall. When challenged with angiotensin II, these mice developed aortic aneurysm, dissection, and rupture with features similar to those in humans, in both thoracic and abdominal segments. Aortas from Akt2-deficient mice displayed profound tissue destruction, apoptotic cell death, and inflammatory cell infiltration that were not observed in aortas from wild-type mice. In addition, angiotensin II-infused Akt2-deficient mice showed significantly elevated expression of matrix metalloproteinase-9 (MMP-9) and reduced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). In cultured human aortic vascular smooth muscle cells, AKT2 inhibited the expression of MMP-9 and stimulated the expression of TIMP-1 by preventing the binding of transcription factor forkhead box protein O1 to the MMP-9 and TIMP-1 promoters.

Conclusions: Impaired AKT2 signaling may contribute to increased susceptibility to the development of AAD. Our findings provide evidence of a mechanism that underlies the protective effects of AKT2 on the aortic wall and that may serve as a therapeutic target in the prevention of AAD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aneurysm, Dissecting / enzymology*
  • Aneurysm, Dissecting / etiology
  • Aneurysm, Dissecting / prevention & control
  • Angiotensin II / pharmacology
  • Angiotensin II / toxicity
  • Animals
  • Aorta, Thoracic / enzymology
  • Aorta, Thoracic / pathology
  • Aortic Aneurysm, Thoracic / enzymology*
  • Aortic Aneurysm, Thoracic / etiology
  • Aortic Aneurysm, Thoracic / prevention & control
  • Aortitis / chemically induced
  • Aortitis / enzymology
  • Aortitis / genetics
  • Aortitis / pathology
  • Apoptosis / drug effects
  • Case-Control Studies
  • Cells, Cultured / drug effects
  • Cells, Cultured / enzymology
  • Elastic Tissue / pathology
  • Enzyme Induction
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / antagonists & inhibitors
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / enzymology
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt / deficiency
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / physiology*
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
  • Tissue Inhibitor of Metalloproteinase-1 / genetics

Substances

  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • TIMP1 protein, human
  • Timp1 protein, mouse
  • Tissue Inhibitor of Metalloproteinase-1
  • Angiotensin II
  • AKT2 protein, human
  • Akt2 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Matrix Metalloproteinase 9