Journal
ATHEROSCLEROSIS
Volume 194, Issue 1, Pages 125-133Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2006.10.013
Keywords
angiotensin II interleukin-6; STAT3; atherosclerosis; LDL receptor knock-out mouse; cytokine; inflammation
Funding
- NHLBI NIH HHS [HL70925, R01 HL070925-04, R01 HL070925] Funding Source: Medline
- PHS HHS [NIEHS T32-07254] Funding Source: Medline
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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 during 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 for 7 weeks. Equal blood pressures and elevations in serum lipids were seen in both groups. Mice were sacrificed when significant A-II-induced plaque development was first detectable, 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. Local IL-6 production was confirmed by in situ mRNA hybridization and immunostaining, where the most abundant IL-6 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-Tyr(705)-STAT3 formation in the adventitia and endothelium (of IL-6(+/+)mice only). These findings define cytokine profiles in the A-II infusion model and demonstrate that IL-6, produced by activated macrophages and fibroblasts in the adventitia, induces the Jak-STAT3 pathway during early A-II-induced atherosclerosis. (C) 2006 Elsevier Ireland Ltd. All rights reserved.
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