Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice

Recinos, Adrian; LeJeune, Wanda S.; Sun, Hong; Lee, Chang Y.; Tieu, Brian C.; Lu, Muping; Hou, Tieying; Boldogh, Istvan; Tilton, Ronald G.; Brasier, Allan R.

doi:10.1016/j.atherosclerosis.2006.10.013

« Previous Next »Atherosclerosis
Volume 194, Issue 1 , Pages 125-133, September 2007

Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice

Adrian Recinos III
- Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
- Corresponding author at: Division of Endocrinology, MRB 8.138, University of Texas Medical Branch, Galveston, 301 University Blvd., Galveston, TX 77555-1060, USA. Tel.: +1 409 772 2824; fax: +1 409 772 8709.
Wanda S. LeJeune
- Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
Hong Sun
- Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
Chang Y. Lee
- Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
Brian C. Tieu
- Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
Muping Lu
- Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
Tieying Hou
- Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
Istvan Boldogh
- Department Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Ronald G. Tilton
- Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
- Stark Diabetes Center, University of Texas Medical Branch, Galveston, TX 77555, USA
Allan R. Brasier
- Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
- Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, TX 77555, USA

Received 10 March 2006; received in revised form 25 September 2006; accepted 6 October 2006. published online 17 November 2006.

Abstract

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-Tyr⁷⁰⁵-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.

Keywords: Angiotensin II, Interleukin-6, STAT3, Atherosclerosis, LDL receptor knock-out mouse, Cytokine, Inflammation