Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3

• Published in: Journal of molecular and cellular cardiology Vol. 87; pp. 160 - 170
• Main Authors: Qin, Zhexue, Bagley, Jessamyn, Sukhova, Galina, Baur, Wendy E., Park, Ho-Jin, Beasley, Debbie, Libby, Peter, Zhang, Yali, Galper, Jonas B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2015
• Subjects: Abdominal aortic aneurysm; Angiotensin II; Angiotensin II - toxicity; Animals; Aortic Aneurysm, Abdominal - chemically induced; Aortic Aneurysm, Abdominal - genetics; Aortic Aneurysm, Abdominal - pathology; Apolipoproteins E - genetics; Cardiovascular; Disease Models, Animal; Gene Expression Regulation; Humans; Macrophages - metabolism; Macrophages - pathology; Male; Mice; Mice, Knockout; Signal Transduction; STAT3; STAT3 Transcription Factor - biosynthesis; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Toll-like receptor 4; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Angiotensin II; Abdominal aortic aneurysm; Toll-like receptor 4; STAT3
• ISSN: 0022-2828; 1095-8584; 1095-8584
• DOI: 10.1016/j.yjmcc.2015.08.014

Abdominal Aortic Aneurysm (AAA) is a major cause of mortality and morbidity in men over 65years of age. Male apolipoprotein E knockout (ApoE−/−) mice infused with angiotensin II (AngII) develop AAA. Although AngII stimulates both JAK/STAT and Toll-like receptor 4 (TLR4) signaling pathways, their involvement in AngII mediated AAA formation is unclear. Here we used the small molecule STAT3 inhibitor, S3I-201, the TLR4 inhibitor Eritoran and ApoE−/−TLR4−/− mice to evaluate the interaction between STAT3 and TLR4 signaling in AngII-induced AAA formation. ApoE−/− mice infused for 28days with AngII developed AAAs and increased STAT3 activation and TLR4 expression. Moreover, AngII increased macrophage infiltration and the ratio of M1 (pro-inflammatory)/M2 (healing) macrophages in aneurysmal tissue as early as 7–10days after AngII infusion. STAT3 inhibition with S3I-201 decreased the incidence and severity of AngII-induced AAA formation and decreased MMP activity and the ratio of M1/M2 macrophages. Furthermore, AngII-mediated AAA formation, MMP secretion, STAT3 phosphorylation and the ratio of M1/M2 macrophages were markedly decreased in ApoE−/−TLR4−/− mice, and in Eritoran-treated ApoE−/− mice. TLR4 and pSTAT3 levels were also increased in human aneurysmal tissue. These data support a role of pSTAT3 in TLR4 dependent AAA formation and possible therapeutic roles for TLR4 and/or STAT3 inhibition in AAA. •By using AngII induced AAA formation in the ApoE-/- mice, we demonstrate that AngII mediated AAA is in part dependent on the STAT3 via TLR4.•We offer evidence that small molecule STAT3 inhibitor, S3I-201, and the TLR4 inhibitor, Eritoran, markedly attenuate AAA formation in this model.•We demonstrate the role of STAT3 and TLR4 in macrophage infiltration and the ratio of M1/M2 macrophages during AAA formation.