Abstract 1147: Angiotensin II Induces IL-6 Expression and the JAK-STAT3 Pathway in Aortic Adventitia of LDL Receptor-Deficient Mice
Angiotensin II (A-II), the major effector peptide of the renin angiotensin system, potently accelerates progression of atherosclerosis. To investigate its effects on vascular inflammatory mechanisms, we elucidated vascular cytokine expression in early lesion development in A-II-infused atherosclerosis-prone LDLR −/− mice. Male LDLR−/− mice were placed on a “Western” high-fat diet for 4 weeks, followed by sham or A-II infusion (620 ng/min/kg) for 7 weeks. Equal blood pressures and elevations in serum lipids were seen in both groups. Mice were sacrificed when significant AII-induced atherosclerotic plaque development was first detectable. A-II infusion (versus sham infusion) increased mean aortic lesion areas from 4.3 (± 1.6) to 22.9 (± 7.3) % [P < 10−6]. Aortae were explanted and culture media assayed for secreted cytokines. Nine cytokines were significantly induced with interleukin-6 (IL-6) being the most highly secreted (Table⇓). Local IL-6 production was confirmed by in situ mRNA hybridization and by immunostaining, where the most predominant secretion was found in the aortic adventitia, with lesser production by the medial and intimal layers. Immunofluorescence colocalization showed IL-6 expression by fibroblasts and activated macrophages. Activation of downstream IL-6 signaling mediated by the Jak-STAT3 pathway was demonstrated by inducible phospho-Tyr705-STAT3 formation in the adventitia and endothelium. This phospho-STAT3 signaling was IL-6-dependent as it was not observed in similarly treated LDLR−/− / IL-6−/−double-null mice. These findings define cytokine secretion profiles in the A-II infusion mouse model and demonstrate that IL-6, produced by activated macrophages and fibroblasts in the aortic adventitia, induces the Jak-STAT3 pathway early in A-II-induced atherosclerosis.