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A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy.

ABSTRACT: Abdominal Aortic aneurysm (AAA) is associated with chronic inflammation, cells apoptosis, and impairment of autophagy. BP-1-102, a novel potent STAT3 inhibitor, has been recently reported to significantly block inflammation-related signaling pathways of JAK2/STAT3 and NF-?B, as well as regulate autophagy. However, its role in vascular inflammation and AAA progression remains to be elucidated. In the present study, the effect and potential mechanisms of BP-1-102 on angiotensin II (AngII) induced AAA in ApoE-/- mice were investigated. AAA was induced in ApoE-/- mice with infusion of AngII for 28 days. BP-1-102 was administrated orally to mice every other day. Mice were sacrificed on day 7, day 14, and day 28 to evaluate the treatment effects. BP-1-102 markedly decreased AAA incidence and aortic diameter, maintained elastin structure and volume, reduced the expression of pro-inflammatory cytokines and MMPs, and inhibited inflammatory cells infiltration. Moreover, BP-1-102 dramatically reduced the expression of JAK2, p-STAT3, p-NF-?B, and Bcl-xL but maintained the expression of LC3B and Beclin in AAA tissues. In vitro, vascular smooth muscle cells (VSMCs) were treated with AngII and/or BP-1-102 at indicated time and concentration. BP-1-102 inhibited AngII-induced JAK2/STAT3 and NF-?B signaling activation and maintained autophagy-related proteins expression in VSMCs. Taken together, our findings suggest that BP-1-102 inhibits vascular inflammation and AAA progression through decreasing JAK2/STAT3 and NF-?B activation and maintaining autophagy.

SUBMITTER: Wu QY

PROVIDER: S-EPMC7028955 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy.

Wu Qi-Ying QY Cheng Zhao Z Zhou Yang-Zhao YZ Zhao Yuan Y Li Jian-Ming JM Zhou Xin-Min XM Peng Hong-Ling HL Zhang Guang-Sheng GS Liao Xiao-Bo XB Fu Xian-Ming XM

Cell death & disease 20200218 2

Abdominal Aortic aneurysm (AAA) is associated with chronic inflammation, cells apoptosis, and impairment of autophagy. BP-1-102, a novel potent STAT3 inhibitor, has been recently reported to significantly block inflammation-related signaling pathways of JAK2/STAT3 and NF-κB, as well as regulate autophagy. However, its role in vascular inflammation and AAA progression remains to be elucidated. In the present study, the effect and potential mechanisms of BP-1-102 on angiotensin II (AngII) induced ...[more]

PMID: 32071300

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Project description:AimsAbdominal aortic aneurysm (AAA) is one of the number of diseases associated with a prominent inflammatory cell infiltration, matrix protein degradation, and smooth muscle cell apoptosis. CD95 is an inflammatory mediator and an apoptosis inducer. Previous studies have shown elevated expression of CD95 or CD95L in the aortic tissue of AAA patients. However, how the CD95L/CD95 contributes to aneurysm degeneration and whether blocking its signalling would be beneficial to disease progression remains largely unknown. In the present study, we sought to determine the role of CD95L and its downstream target, caspase 8, in AAA progression.Methods and resultsBy using the CaCl2 murine model of AAA, abdominal aortic aneurysms were induced in C57BL/6 mice. We found that both mRNA and protein levels of CD95L were increased in aneurysm tissue compared with NaCl-treated normal aortic tissue. To determine whether CD95L contributes directly to aneurysm formation, we used CD95L null (CD95L-/-) mice to examine their response to CaCl2 aneurysm induction. Six weeks after periaortic application of CaCl2, aortic diameters of CD95L-/- mice were significantly smaller compared to CaCl2-treated wild-type controls. Connective tissue staining of aortic sections from CaCl2-treated CD95L-/- mice showed minimal damage of medial elastic lamellae which was indistinguishable from the NaCl-treated sham control. Furthermore, CD95L deficiency attenuates macrophage and T cell infiltration into the aortic tissue. To study the role of CD95L in the myelogeous cells in AAA formation, we created chimaeric mice by infusing CD95L-/- bone marrow into sub-leathally irradiated wild-type mice (WT/CD95L-/-BM). As controls, wild-type bone marrow were infused into sub-leathally irradiated CD95L-/- mice (CD95L-/-/WTBM). WT/CD95L-/-BM mice were resistant to aneurysm formation compared to their controls. Inflammatory cell infiltration was blocked by the deletion of CD95L on myeloid cells. Western blot analysis showed the levels of caspase 8 in the aortas of CaCl2-treated wild-type mice were increased compared to NaCl-treated controls. CD95L deletion inhibited caspase 8 expression. Furthermore, a caspase 8-specific inhibitor was able to partially block aneurysm development in CaCl2-treated aneurysm models.ConclusionThese studies demonstrated that inflammatory cell infiltration during AAA formation is dependent on CD95L from myelogeous cells. Aneurysm inhibition by deletion of CD95L is mediated in part by down-regulation of caspase 8.

Project description:BackgroundAbdominal aortic aneurysm (AAA), a degenerative vascular pathology characterized by permanent dilation of the aorta, is considered a chronic inflammatory disease involving innate/adaptive immunity. However, the functional role of antibody-dependent immune response against antigens present in the damaged vessel remains unresolved. We hypothesized that engagement of immunoglobulin G (IgG) Fc receptors (FcγR) by immune complexes (IC) in the aortic wall contributes to AAA development. We therefore evaluated FcγR expression in AAA lesions and analysed whether inhibition of FcγR signaling molecules (γ-chain and Syk kinase) influences AAA formation in mice.MethodsFcγR gene/protein expression was assessed in human and mouse AAA tissues. Experimental AAA was induced by aortic elastase perfusion in wild-type (WT) mice and γ-chain knockout (γKO) mice (devoid of activating FcγR) in combination with macrophage adoptive transfer or Syk inhibitor treatment. To verify the mechanisms of FcγR in vitro, vascular smooth muscle cells (VSMC) and macrophages were stimulated with IgG IC.ResultsFcγR overexpression was detected in adventitia and media layers of human and mouse AAA. Elastase-perfused γKO mice exhibited a decrease in AAA incidence, aortic dilation, elastin degradation, and VSMC loss. This was associated with (1) reduced infiltrating leukocytes and immune deposits in AAA lesions, (2) inflammatory genes and metalloproteinases downregulation, (3) redox balance restoration, and (4) converse phenotype of anti-inflammatory macrophage M2 and contractile VSMC. Adoptive transfer of FcγR-expressing macrophages aggravated aneurysm in γKO mice. In vitro, FcγR deficiency attenuated inflammatory gene expression, oxidative stress, and phenotypic switch triggered by IC. Additionally, Syk inhibition prevented IC-mediated cell responses, reduced inflammation, and mitigated AAA formation.ConclusionOur findings provide insight into the role and mechanisms mediating IgG-FcγR-associated inflammation and aortic wall injury in AAA, which might represent therapeutic targets against AAA disease.

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A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy.

Publications

A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy.

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