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Loss of STAT1 is associated with increased aortic rupture in an experimental model of aortic dissection and aneurysm formation  Matthew J. Eagleton, MD,

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Presentation on theme: "Loss of STAT1 is associated with increased aortic rupture in an experimental model of aortic dissection and aneurysm formation  Matthew J. Eagleton, MD,"— Presentation transcript:

1 Loss of STAT1 is associated with increased aortic rupture in an experimental model of aortic dissection and aneurysm formation  Matthew J. Eagleton, MD, Jun Xu, BS, Mingfang Liao, MD, Brittney Parine, BS, Guy M. Chisolm, PhD, Linda M. Graham, MD  Journal of Vascular Surgery  Volume 51, Issue 4, Pages (April 2010) DOI: /j.jvs Copyright © 2010 Society for Vascular Surgery Terms and Conditions

2 Fig 1 A, Representative immunoblots show the assessment of tyrosine-, serine-, and total signal transducer and activator of transcription 1 (STAT1) from human aortic homogenates in those with abdominal aortic aneurysm (AAA) and those without aneurysms (NA). β-actin was also assayed in these samples. B, Graph demonstrates the fraction of STAT1 in the tyrosine- and serine-phosphorylated form. Although there were no changes in the fraction of STAT1 in the different phosphorylated forms, there was a significant increase in total STAT1 protein from those with abdominal aortic aneurysm (AAA, grey bars) vs those without aneurysm (NA, black bars; *P < .05). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

3 Fig 2 Graph presents temporal changes in aortic total signal transducer and activator of transcription 1 (STAT1) protein (black bars) and activated STAT1 protein (grey bars) and STAT1 messenger RNA from mice undergoing angiotensin (Ang) II infusion (n = 8/time point). Changes are normalized to baseline aortic levels. Although there was a trend in a decrease in total STAT1 during the first 2 weeks of Ang II infusion, this did not reach statistical significance. There was, however, a significant increase in the fraction of STAT1 in the active form (both serine- and tyrosine-phosphorylated STAT1), peaking at 7 days of Ang II infusion (*P < .01). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

4 Fig 3 Representative immunohistochemical analysis of an apolipoprotein E null mouse aorta harvested at 7 days of angiotensin II infusion. A, At 7 days there is evidence of an aortic dissection with a false lumen (FL) and patent true lumen (TL; original magnification ×20). Immunohistochemical staining for tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) was performed, and regions of the aorta bordering the false lumen (B) and the true lumen (C) were evaluated under higher magnification (original magnification ×100). B, Inflammatory cells infiltrating the false lumen (FL) stain positively (arrow) for tyrosine-phosphorylated STAT1. C, No positive staining is observed along the true lumen (TL) border. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

5 Fig 4 A, Aortic diameters are shown from male and female apolipoprotein E (ApoE)-/-, signal transducer and activator of transcription 1 (STAT1)-/-, and ApoE/STAT1-/- mice after 28 days of angiotensin (Ang) II infusion. No significant aortic enlargements observed in STAT1-/- male mice or in any of the female mice strains after 28 days of Ang II infusion. Aortic enlargement was observed in male ApoE-/- and male ApoE/STAT1-/- mice, and was larger in the ApoE/STAT1-/- mice compared with the ApoE-/- mice (*P < .05). B, Graph presents aortic aneurysm morphology identified in ApoE-/- male mice (black bars) and ApoE/STAT1-/- male mice (clear bars). All ApoE/STAT1 null mice developed the type IV phenotype. C, Examples of aortas resected from (a) an ApoE-/- mouse that did not undergo Ang II infusion, (b) an ApoE-/- mouse that developed a type II morphology aneurysm, and (c) an ApoE/STAT1-/- mouse that developed a type IV morphology aneurysm. The upward pointing arrows in all three instances denote the location of the right renal artery, and the block triangles point to locations of aneurysmal degeneration (only b and c). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

6 Fig 5 Representative sections of histologic analysis of (A, B) elastin content with Movat stain and (B, D) collagen content with trichrome stain from the aortic walls of (A, C) apolipoprotein E (ApoE)/signal transducer and activator of transcription 1 (STAT1) null mice and (B, D) ApoE null mice (original magnification ×100). No differences in elastic lamellae, elastin deposition, or collagen deposition are seen at baseline between these two mouse strains. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

7 Fig 6 A, Representative gelatin zymograms from aortic homogenates from apolipoprotein E (ApoE)-/-, signal transducer and activator of transcription (STAT1)-/-, and ApoE/STAT1-/- mice at baseline or after 8 days of angiotensin (Ang) II infusion. The 92 kDa protein corresponds to pro-matrix metalloproteinase (MMP)-9 and the 72 kDa protein corresponds to pro-MMP-2. B, Graphic shows total MMP-2 and MMP-9 expression in ApoE -/- (black bars) and ApoE/STAT1-/- (grey bars) mice at baseline assessed by gelatin zymography and reverse transcriptase-polymerase chain reaction (n = 5 mice/strain). Results are expressed relative to expression in ApoE-/- mice. There is no significant difference in MMP activity or messenger RNA levels at baseline in these strains. C, Graph represents MMP-2 and MMP-9 activity (assessed by gelatin zymography) from aortic homogenates obtained from ApoE-/- (black bars), ApoE/STAT1-/- (gray bars), and STAT1-/- (white bars) after 28 days of Ang II infusion (n = 5 mice/strain). Results are expressed normalized to corresponding strains at baseline. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

8 Fig 7 Graph shows total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) from apolipoprotein E (ApoE) null mice and ApoE/signal transducer and activator of transcription (STAT1) double-null mice. Total cholesterol levels are higher in the ApoE/STAT1 double-null mice compared with ApoE null mice (*P < .04). HDL and LDL levels did not differ between these two mouse strains. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

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