(480.2) Abdominal Aortic Aneurysm and Plasminogen Activator Inhibitor 1: Correlation in the Context of Type 2 Diabetes

Poster Board Number: C94
Introduction: AAA has separate poster presentation times for odd and even posters.
Odd poster #s – 10:15 am – 11:15 am
Even poster #s – 11:15 am – 12:15 pm

Kathryn Jespersen (University of Nebraska Medical Center), Trevor Meisinger (University of Nebraska Medical Center), Wanfen Xiong (University of Nebraska Medical Center), Bernard Baxter (University of Nebraska Medical Center)

Background.  Abdominal Aortic Aneurysm (AAA) is a progressive, inflammatory disease of the infrarenal aorta, characterized by irreversible aortic dilation.  Despite decades of research, AAA pathogenesis remains poorly understood, and no pharmaceutical therapies to slow aortic growth have been identified.  Interestingly, the only condition known to be associated with decreased rates of aortic growth and rupture in AAA patients is a diagnosis of Type 2 Diabetes Mellitus (T2DM).  Our laboratory has demonstrated that streptozotocin (STZ)-induced hyperglycemia inhibits aortic dilation in a mouse model of AAA.  Plasminogen Activator Inhibitor 1 (PAI-1), a key player in the fibrinolytic pathway, has been shown to be elevated in both Type 1 and T2DM patients and hyperglycemic mice.  Additionally, studies have demonstrated that local application of PAI-1 is effective in inhibiting AAA development in a murine model.

Objective. The purpose of the present study was to determine the role of PAI-1 expression in hyperglycemic protection against AAA growth.

Hypothesis. We predicted that elevated PAI-1 is responsible for decreased fibrinolysis leading to inhibited aortic growth in patients with both diabetes and AAA.  Based on this hypothesis, we proposed that hyperglycemic mice deficient in PAI-1 (PAI-1 KO) would not demonstrate the protection from AAA growth observed in hyperglycemic C57BL/6J (C57) control mice.

Methods.  Fasting blood glucose (BG; mg/dL) was measured in 6-week-old C57 and PAI-1 KO mice at baseline on experimental day (D)0, and STZ (40 mg/kg) was intraperitoneally administered daily from D0 to D4.  Sodium citrate buffer (SC; vehicle) was administered to control mice.  On D14, final BG was measured to confirm hyperglycemia (≥250 mg/dL).  On D21, mice underwent laparotomy: a midline abdominal incision was made and the infrarenal aorta was isolated.  After measuring aortic diameter midway between the renal arteries and iliac bifurcation, pancreatic porcine elastase (PPE; 60 U/mL) was applied to the adventitial aorta for 5 minutes.  The aorta and surrounding structures were then washed twice with 0.9% sterile saline.  Control mice received heat-inactivated PPE.  On D49, the incision was reopened, and the aorta was isolated and measured at the widest point of dilation.

Results.  STZ-treated C57 mice experienced significantly reduced AAA diameter compared to SC-treated C57 controls (p lt; 0.0001) 4 weeks post-induction.  However, differences in AAA diameter were not observed under the same treatment conditions in PAI-1 KO mice (p = 0.290).  Percent increase in aortic diameter in both STZ- and SC-treated PAI-1 KO mice induced with AAA was significantly reduced compared to that of SC-treated C57 mice (p lt; 0.01 and p lt; 0.0001, respectively). Conclusions.  Our study demonstrated that PAI-1 is elevated in mice with STZ-induced diabetes.  While hyperglycemic mice show significantly reduced AAA growth compared to normoglycemic AAA controls, no difference in aortic growth is observed between hyperglycemic and normoglycemic PAI-1 KO mice.  Regardless of treatment status, PAI-1 deficient mice experience significantly reduced AAA growth compared to C57 control mice.  We conclude that while the fibrinolytic pathway and PAI-1 are influential in AAA development, hyperglycemia-induced elevated PAI-1 expression does not play a crucial role in hyperglycemic inhibition of AAA growth.  Conversely, PAI-1 deficiency appears to inhibit AAA growth regardless of glycemic status.