Abstract 1204: Angiotensin II-induced Abdominal Aortic Aneurysms Are Attenuated By Deficiency Of The Innate Immune Mediator, Myeloid Differentiation Factor 88
Objective: Angiotensin II (AngII) infusion into hypercholesterolemic mice enhances the formation of atherosclerotic lesions and induces abdominal aortic aneurysms (AAAs). Both pathologies are characterized by an infiltration of macrophages. Attenuation of macrophage function by deficiency of myeloid differentiation factor 88 (MyD88) decreases hypercholesterolemia-induced atherosclerosis. The purpose of this study was to determine the effects of MyD88 deficiency on AngII-induced vascular pathologies.
Methods and Results: Immunostaining of AngII-induced atherosclerosis and AAAs demonstrated the expression of MyD88 in both vascular pathologies that colocalized with macrophages. To demonstrate the functional role of MyD88 in the development of AngII-induced vascular disease, male apoE−/−mice that were either MyD88+/+ (n=17) or −/− (n=15) were fed a normal diet and administered with angiotensin II (1,000 ng/kg/min by osmotic minipump) for 28 days. AngII increased systolic blood pressure similarly in both groups (+/+; pre-infusion 112 ± 5, post-infusion 171 ± 3 mmHg: −/− ; pre-infusion 116 ± 4; post-infusion 173 ± 3 mmHg) and renin was decreased markedly (Controls ; 9.64 ± 1.87 ng/ml compared to AngII-infused -+/+; 0.81 ± 0.6 : −/− ; 2.94 ± 0.97 ng/ml). MyD88 genotype or AngII infusions had no significant effects on total plasma cholesterol concentrations or lipoprotein-cholesterol distributions. Similar to cholesterol-induced atherosclerosis, MyD88 decreased the size of AngII-induced atherosclerotic lesions in aortic roots (+/+; 0.00621 ± 0.0019; −/−; 0.00218 ± 0.0011 mm2, n=5 per group). MyD88 deficiency decreased the diameter of the aneurysmal region from 1.50 ± 0.18 to 0.97 ± 0.08 mm (P < 0.001) and the incidence of AAAs from 76% to 13% (P<0.01).
Conclusion: The deficiency MyD88 markedly decreased the development of angiotensin II-induced AAAs, consistent with a role of Toll-like receptors in the development of disease process.