Loss of STAT1 is associated with increased aortic rupture in an experimental model of aortic dissection and aneurysm formation

BackgroundTranscription factor signal transducer and activator of transcription (STAT) 1 has been linked to a variety of pathologic states involved with matrix remodeling, but its role in aortic pathology has not been previously described. The current study hypothesized that STAT1 regulates aneurysmal degeneration and its role was evaluated in human abdominal aortic aneurysm (AAA) and in a mouse model of aortic dissection.MethodsApolipoprotein E knockout mice (ApoE-/-) or ApoE/STAT1 double knockout mice (ApoE/STAT1-/-) were infused with 1000 ng/kg/min of angiotensin II. Systolic blood pressure (SBP) was measured in the rodent tail. At sacrifice, aortic diameters and extent of aneurysm formation were measured by digital microscopy. STAT1 and phosphorylated-STAT1 protein levels were assessed in ApoE-/- mice at 0, 7, 14, and 28 days (n = 8/time point) by enzyme-linked immunosorbent assay. Histology was performed using hematoxylin and eosin (H&E) and Movat stains. Statistical analyses included χ2 test, t test, and analysis of variance.ResultsSTAT1 messenger RNA and total protein were greater in human AAA vs non-AAA controls. In addition, aneurysms occurred in 8%, 50%, and 80% of ApoE-/- mice at 7, 14, and 28 days, respectively. Total STAT1 levels were not altered during the course of angiotensin II infusion. Phosphorylated STAT1 levels peaked at 7 days with a 1.4-fold increase over baseline (P < .05). Aneurysms occurred in 0%, 100%, and 100% of ApoE/STAT1-/- mice at 3, 5, and 28 days. In mice infused with angiotensin II for >3 days, aortic rupture occurred more frequently in ApoE/STAT-/- mice (53% vs 19%, P < .05) and at earlier time points (4.0 ± 0.5 vs 9.2 ± 0.77 days, P < .05) vs ApoE-/- mice. SBP did not differ between the groups during angiotensin II infusion. By 28 days, aneurysms were larger in ApoE/STAT1-/- mice compared with ApoE-/- mice (2.7 ± 0.4 vs 1.9 ± 0.1 mm, P < .05) and were more extensive. H&E and Movat stain did not reveal differences in aortic wall structural content at baseline between ApoE-/- and ApoE/STAT1-/- mice. Both groups demonstrated equal disorganization in the aneurysmal state.ConclusionsPhosphorylated STAT1 is elevated during aneurysmal degeneration. Its loss is associated with a higher rate of acute aortic rupture and more extensive aneurysms in a mouse model of aortic dissection. Further investigation is necessary to determine whether these observations are secondary to an underlying aortic wall abnormality or alterations in vessel wall matrix remodeling.

Clinical RelevanceAbdominal aortic aneurysms (AAA) are a major health concern. Age, smoking, hypercholesterolemia, family history of AAA, and atherosclerotic disease all correlate with an increased risk for the development of aortic aneurysms. Most AAAs remain undetected until the aneurysm presents with a rupture or is identified incidentally. Currently, the only mode of treatment is operative intervention by conventional or endovascular surgery before significant aneurysm expansion and rupture. Future improvement in outcomes for patients with aneurysmal disease will involve the early identification of patients prone to develop AAA and those with small, low-risk aneurysms. Pharmacologic therapy to prevent aortic wall deterioration and subsequent aneurysm formation in this group would prove extraordinarily beneficial. A better understanding of the sequence of biochemical and cellular events that lead to AAA formation would allow the development of pharmacotherapies targeted at preventing aneurysm development and expansion.