title: Phosphorylation of AKT and abdominal aortic aneurysm formation.
abstract: It is hypothesized that differential AKT phosphorylation between sexes is important in abdominal aortic aneurysm (AAA) formation. Male C57BL/6 mice undergoing elastase treatment showed a typical AAA phenotype (80% over baseline, P < 0.001) and significantly increased phosphorylated AKT-308 (p308) and total-AKT (T-AKT) at day 14 compared with female mice. Elastase-treated Raw cells produced increased p308 and significant amounts of matrix metalloproteinase 9 (MMP-9), and these effects were suppressed by LY294002 treatment, a known AKT inhibitor. Male and female rat aortic smooth muscle cells treated with elastase for 1, 6, or 24 hours demonstrated that the p308/T-AKT and AKT-Ser-473/T-AKT ratios peaked at 6 hours and were significantly higher in the elastase-treated cells compared with controls. Similarly, male cells had higher phosphorylated AKT/T-AKT levels than female cells. LY294002 also inhibited elastase-induced p308 formation more in female smooth muscle cells than in males, and the corresponding cell media had less pro-MMP-9. AKT siRNA significantly decreased secretion of pro-MMP-9, as well as pro-MMP-2 and active MMP-2 from elastase-treated male rat aortic smooth muscle cells. IHC of male mice AAA aortas showed increased p308, AKT-Ser-473, and T-AKT compared with female mice. Aortas from male AAA patients had a significantly higher p308/T-AKT ratio than female AAA tissues. These data suggest that AKT phosphorylation is important in the upstream regulation of MMP activity, and that differential phosphorylation may be important in sex differences in AAA.
authors: Section of Vascular Surgery, Department of Surgery, Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan.
authors: Abhijit
authors: A
authors: Ghosh
authors: Division of Vascular and Endovascular Surgery, University of Virginia, Charlottesville, Virginia.
authors: Guanyi
authors: G
authors: Lu
authors: Division of Vascular and Endovascular Surgery, University of Virginia, Charlottesville, Virginia.
authors: Gang
authors: G
authors: Su
authors: Section of Vascular Surgery, Department of Surgery, Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan.
authors: Brendan
authors: B
authors: McEvoy
authors: Section of Vascular Surgery, Department of Surgery, Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan.
authors: Omar
authors: O
authors: Sadiq
authors: Section of Vascular Surgery, Department of Surgery, Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan.
authors: Paul D
authors: PD
authors: DiMusto
authors: Section of Vascular Surgery, Department of Surgery, Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan.
authors: Adriana
authors: A
authors: Laser
authors: Section of Vascular Surgery, Department of Surgery, Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan.
authors: John S
authors: JS
authors: Futchko
authors: Section of Vascular Surgery, Department of Surgery, Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan.
authors: Peter K
authors: PK
authors: Henke
authors: Section of Vascular Surgery, Department of Surgery, Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan.
authors: Jonathan L
authors: JL
authors: Eliason
authors: Division of Vascular and Endovascular Surgery, University of Virginia, Charlottesville, Virginia. Electronic address: gru6n@virginia.edu.
authors: Gilbert R
authors: GR
authors: Upchurch
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering; D012727:Sex Characteristics; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9