title: Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3.
abstract: Abdominal Aortic Aneurysm (AAA) is a major cause of mortality and morbidity in men over 65 years 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 28 days 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 7-10 days 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.
authors: Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA; Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors: Zhexue
authors: Z
authors: Qin
authors: Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
authors: Jessamyn
authors: J
authors: Bagley
authors: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02113, USA.
authors: Galina
authors: G
authors: Sukhova
authors: Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
authors: Wendy E
authors: WE
authors: Baur
authors: Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
authors: Ho-Jin
authors: HJ
authors: Park
authors: Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
authors: Debbie
authors: D
authors: Beasley
authors: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02113, USA.
authors: Peter
authors: P
authors: Libby
authors: Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA. Electronic address: yzhang2@tuftsmedicalcenter.org.
authors: Yali
authors: Y
authors: Zhang
authors: Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA; Cardiovascular Center, Division of Cardiology, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA. Electronic address: jgalper@tuftsmedicalcenter.org.
authors: Jonas B
authors: JB
authors: Galper
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000804:Angiotensin II
keywords: Abdominal aortic aneurysm; Angiotensin II; STAT3; Toll-like receptor 4