Angiotensin-Induced Abdominal Aortic Aneurysms in Hypercholesterolemic Mice: Role of Serum Cholesterol and Temporal Effects of Exposure

Petra A Prins,Macrae F Linton,Sergio Fazio,Prudhvidhar R Perati,Uchechukwu K Sampson,Sam Nwosu,Michael F Hill,Hagai Tavori,Valentina Kon,David Airey,Michael Bader

doi:10.1371/journal.pone.0084517

Abstract

ObjectiveUnderstanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E−/− mice.ApproachA cohort of mice underwent a 4-week pump-mediated infusion of saline (n = 23) or 1500 ng/kg/min of Ang II (n = 85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for hemodynamic covariates in the regression models for AAA occurrence in relation to time.ResultsThe overall effect of time was statistically significant (p<0.001). Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (−0.234, p = 0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p<0.001) and 2.35 (p = 0.04), respectively. Hemodynamic parameters were not predictive of change in aortic diameter (Δ) (SBP, p = 0.66; DBP, p = 0.66). Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p<0.0001), and the difference was due to LDL. AngII exposure was associated with 0.43 mm (95% CI, 0.27 to 0.61, p<0.0001) increase in aortic diameter; and a 100 mg/dl increase in mean final cholesterol level was associated with a 12% (95% CI, 5.68 to 18.23, p<0.0001) increase in aortic diameter. Baseline cholesterol was not associated with change in aortic diameter (p = 0.86).ConclusionsThese are the first formal estimates of a consistent pattern of Ang II-induced AAA development. The odds of AAA occurrence diminish after the second week of Ang II infusion, and TC is independently associated with AAA size.

Highlights

Angiotensin II (AngII)-induced models of abdominal aortic aneurysms (AAA) constitute the bedrock of experimental strategies to elucidate the pathobiology of AAA and for the development of therapeutic interventions
Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (20.234, p = 0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p,0.001) and 2.35 (p = 0.04), respectively
Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p,0.0001), and the difference was due to low density lipoprotein (LDL)

Summary

Introduction

Angiotensin II (AngII)-induced models of abdominal aortic aneurysms (AAA) constitute the bedrock of experimental strategies to elucidate the pathobiology of AAA and for the development of therapeutic interventions. AngII-induced model shares similarities with the human disease, the incidence of experimental AAA is reportedly independent of blood pressure and is augmented by hyperlipidemia [2]. Despite widespread employment of this model for the interrogation of the pathobiology of AAA disease processes, there is no apparent reason for the observed diversity in AAA size noted in this model despite controlled experimental conditions [9], nor is there a wellcharacterized pattern of development. In this context, it is not clear whether systemic hemodynamic conditions modulate differences in AAA size and temporal evolution. Hypercholesterolemia is known to augment the incidence of AAA, the relationship between the degree of hypercholesterolemia and the temporal evolution and size of AAA is unknown

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