Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3
Baur, Wendy E.
Galper, Jonas B.
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CitationQin, Zhexue, Jessamyn Bagley, Galina Sukhova, Wendy E. Baur, Ho-Jin Park, Debbie Beasley, Peter Libby, Yali Zhang, and Jonas B. Galper. 2015. “Angiotensin II-Induced TLR4 Mediated Abdominal Aortic Aneurysm in Apolipoprotein E Knockout Mice Is Dependent on STAT3.” Journal of Molecular and Cellular Cardiology 87 (October): 160–170. doi:10.1016/j.yjmcc.2015.08.014.
AbstractAbdominal 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.
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