Elsevier

Surgery

Volume 148, Issue 2, August 2010, Pages 429-435
Surgery

Society of University Surgeon
Hyperglycemia modulates plasminogen activator inhibitor-1 expression and aortic diameter in experimental aortic aneurysm disease

https://doi.org/10.1016/j.surg.2010.05.014Get rights and content

Background

Extracellular matrix degradation is a sentinel pathologic feature of abdominal aortic aneurysm (AAA) disease. Diabetes mellitus, a negative risk factor for AAA, may impair aneurysm progression through its influence on the fibrinolytic system. We hypothesize that hyperglycemia limits AAA progression through effects on endogenous plasminogen activator inhibitor-1 (PAI-1) levels and subsequent reductions in plasmin generation.

Methods

Experimental AAAs were induced in diabetic and control mice via the intra-aortic elastase infusion method. Serial transabdominal high-frequency ultrasound examinations were performed to monitor aortic diameter following elastase infusion. Circulating PAI-1 and plasmin α2-antiplasmin (PAP) complex concentrations were determined by ELISA and local expression of PAI-1 levels was examined by RT-PCR and immunohistochemistry.

Results

Hyperglycemia was associated with reduced AAA diameter, increased plasma PAI-1 concentration and reduced plasmin generation. Aneurysmal aortic PAI-1 gene expression increased in parallel with plasma concentration, with peak expression occurring early after aneurysm initiation.

Conclusion

Hyperglycemia increases PAI-1 expression and attenuates AAA diameter in experimental AAA disease. These results emphasize the role of the fibrinolytic pathway in AAA pathophysiology, and suggest a candidate mechanism for hyperglycemic inhibition of AAA disease.

Section snippets

Experimental models

All animal work was reviewed and approved by the Administrative Panel on Laboratory Animal Care committee at Stanford University. Inhaled isofluorane anesthesia was used for all operative procedures. Hyperglycemia was induced in male C57/BL6 mice (20 to 30g, 10 weeks of age; Jackson Laboratory, Bar Harbor, ME) via consecutive intraperitoneal injection of streptozotocin (STZ: 50 mg/kg; Sigma Aldrich, St. Louis, MO) dissolved in citrate buffer for 5 days as specified by the Animal Models of

AAA diameter is reduced in hyperglycemic mice

Immediately prior to elastase infusion, 3 weeks after initiation of STZ or buffer injections, blood glucose levels in the DM-AAA mice averaged 421 ± 14 mg/dL vs 147 ± 6 mg/dL in AAA mice, P < .05. There was no difference in mean aortic diameter between groups at baseline; DM-AAA mice had significantly decreased aortic diameters at postoperative day (POD) 7 (n = 4) and POD14 (n = 4) compared to AAA mice (also n = 4 at each time point; POD7: DM-AAA 0.92 ± 0.02 mm vs AAA 1.08 ± 0.05 mm, P < .05;

Discussion

Epidemiologic risk factors for AAA disease include advanced age, male gender, cigarette smoking, family history, hypertension, obesity, hypercholesterolemia, and concomitant atherosclerotic disease.7, 8 Although diabetes is a recognized risk factor for most acquired cardiovascular pathologies, recent observations consistently identify a negative association with AAA disease in both men and women.7, 8, 9, 10 The purpose of this study was to examine the influence of serum glucose levels on the

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