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 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.
Recinos
Adrian
A
Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA. a.recinos@utmb.edu
LeJeune
Wanda S
WS
Sun
Hong
H
Lee
Chang Y
CY
Tieu
Brian C
BC
Lu
Muping
M
Hou
Tieying
T
Boldogh
Istvan
I
Tilton
Ronald G
RG
Brasier
Allan R
AR
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D005347:Fibroblasts / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D015850:Interleukin-6; D012333:RNA, Messenger; D011973:Receptors, LDL; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D014443:Tyrosine; D053612:Janus Kinases