Bazedoxifene Attenuates Abdominal Aortic Aneurysm Formation via Downregulation of Interleukin-6/Glycoprotein 130/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Apolipoprotein E–Knockout Mice

Yan, Dan; Ma, Haiying; Shi, Wei; Luo, Pengcheng; Liu, Tianshu; Guo, Junyi; Zhai, Maocai; Tao, Jingwen; Huo, Shengqi; Li, Chenglong; Lin, Jiayuh; Li, Sheng; Lv, Jiagao; Zhang, Cuntai; Lin, Li

doi:10.3389/fphar.2020.00392

Cited by 12 publications

(10 citation statements)

References 36 publications

(52 reference statements)

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“…Using multiple ligand simultaneous docking (MLSD) and drug repositioning, Li et al showed bazedoxifene and raloxifene, which are approved agents for osteoporosis in post-menopausal women with high risk of breast cancer, could inhibit IL-6/glycoprotein 130 interaction resulting in inhibited IL-6 signaling [ 123 ]. These two drugs are found to inhibit IL-6 signaling in tumor and cardiovascular disease including aortic aneurysm [ [124] , [125] , [126] , [127] ], which may also effect in other inflammatory settings. In a randomized, double-blind trial conducted by Ridker PM et al, antiinflammatory treatment by anti-IL-1β antibody canakinumab decreased the rate of recurrent cardiovascular events than placebo [ 128 ].…”

Section: Promising Strategies For Hypercoagulability In Covid-19mentioning

confidence: 99%

Coagulopathy in COVID-19: Focus on vascular thrombotic events

Shi

2020

Journal of Molecular and Cellular Cardiology

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SARS-CoV-2 causes a phenotype of pneumonia with diverse manifestation, which is termed as coronavirus disease 2019 (COVID-19). An impressive high transmission rate allows COVID-19 conferring enormous challenge for clinicians worldwide, and developing to a pandemic level. Combined with a series of complications, a part of COVID-19 patients progress into severe cases, which critically contributes to the risk of fatality. To date, coagulopathy has been found as a prominent feature of COVID-19 and severe coagulation dysfunction may be associated with poor prognosis. Coagulopathy in COVID-19 may predispose patients to hypercoagulability-related disorders including thrombosis and even fatal vascular events. Inflammatory storm, uncontrolled inflammation-mediated endothelial injury and renin angiotensin system (RAS) dysregulation are the potential mechanisms. Ongoing efforts made to develop promising therapies provide several potential strategies for hypercoagulability in COVID-19. In this review, we introduce the clinical features of coagulation and the increased vascular thrombotic risk conferred by coagulopathy according to present reports about COVID-19. The potential underlying mechanisms and emerging therapeutic avenues are discussed, emphasizing an urgent need for effective interventions.

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Section: Promising Strategies For Hypercoagulability In Covid-19mentioning

confidence: 99%

Coagulopathy in COVID-19: Focus on vascular thrombotic events

Shi

2020

Journal of Molecular and Cellular Cardiology

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“…In some inflammatory cardiovascular diseases, expression of IL-6 is dependent on STAT3. Inhibition of STAT3 activation results in reducing the expression of IL-6 in myocardium or blood vessels ( Shi et al, 2020 ; Yan et al, 2020 ). In autoimmune disease, dendritic cells play an indisputable role in instructing the polarization of CD4 + Th17 cells in immune response through generation of cytokines such as IL-6, IL-23, and IL-1β ( Coutant and Miossec, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Bazedoxifene Regulates Th17 Immune Response to Ameliorate Experimental Autoimmune myocarditis via Inhibition of STAT3 Activation

et al. 2021

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Myocarditis is a type of inflammatory cardiomyopathy that has no specific treatment. Accumulating evidence suggests that Th17 cells play a prominent role in the pathogenesis of myocarditis. Interleukin-(IL)-6-mediated signal transducer and activation of transcription 3 (STAT3) signaling is essential for Th17 cell differentiation and secretion of inflammatory cytokines. Bazedoxifene inhibits IL-6/STAT3 signaling in cancer cells, but its effect on the Th17 immune response induced by myocarditis remains unknown. Here we explore the effect of Bazedoxifene on Th17 immune response and cardiac inflammation in a mouse model of experimental autoimmune myocarditis, which has been used to mimic human inflammatory heart disease. After eliciting an immune response, we found Bazedoxifene ameliorated cardiac inflammatory injury and dysfunction. Th17 cells and related inflammatory factors in splenic CD4+ T cells at day 14 and in the heart at day 21 were increased, which were reduced by Bazedoxifene. Furthermore, Bazedoxifene could regulate autophagy induction in polarized Th17 cells. In conclusion, Bazedoxifene affected STAT3 signaling and prevented cardiac inflammation deterioration, so may provide a promising therapeutic strategy for the treatment of experimental autoimmune myocarditis (EAM).

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“…In addition, these infiltrating cells also secrete various inflammatory cytokines, such as IL-1β [34], IL-6 [35], and TNF-α [36], which further drive inflammatory responses and ultimately lead to AAA rupture. Studies have suggested that reducing the activation of these proinflammatory cytokines could inhibit the formation and progression of AAA [34][35][36][37]. Thus, it is clear that therapeutic drugs targeting the inflammatory response can be very effective in improving AAA.…”

Section: Discussionmentioning

confidence: 99%

Silencing IL12p35 Promotes Angiotensin II-Mediated Abdominal Aortic Aneurysm through Activating the STAT4 Pathway

Wang

Dong

et al. 2021

Mediators of Inflammation

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Background and Purpose. Abdominal aortic aneurysm (AAA) is a chronic inflammatory disorder and the important causes of death among men over the age of 65 years. Interleukin-12p35 (IL12p35) is an inflammatory cytokine that participates in a variety of inflammatory diseases. However, the role of IL12p35 in the formation and development of AAA is still unknown. Experimental Approach. Male apolipoprotein E-deficient (Apoe-/-) mice were generated and infused with 1.44 mg/kg angiotensin II (Ang II) per day. We found that IL12p35 expression was noticeably increased in the murine AAA aorta and isolated aortic smooth muscle cells (SMCs) after Ang II stimulation. IL12p35 silencing promoted Ang II-induced AAA formation and rupture in Apoe-/- mice. IL12p35 silencing markedly increased the expression of inflammatory cytokines, including IL-1β, IL-6, and tumor necrosis factor-α (TNF-α), in both the serum and AAA aorta. Additionally, IL12p35 silencing exacerbated SMC apoptosis in Apoe-/- mice after Ang II infusion. IL12p35 silencing significantly increased signal transducer and activator of transcription (STAT) 4 phosphorylation levels in AAA mice, and STAT4 knockdown abolished the IL12p35-mediated proinflammatory response and SMC apoptosis. Interpretation. Silencing IL12p35 promotes AAA formation by activating the STAT4 pathway, and IL12p35 may serve as a novel and promising therapeutic target for AAA treatment.

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Bazedoxifene Attenuates Abdominal Aortic Aneurysm Formation via Downregulation of Interleukin-6/Glycoprotein 130/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Apolipoprotein E–Knockout Mice

Cited by 12 publications

References 36 publications

Coagulopathy in COVID-19: Focus on vascular thrombotic events

Coagulopathy in COVID-19: Focus on vascular thrombotic events

Bazedoxifene Regulates Th17 Immune Response to Ameliorate Experimental Autoimmune myocarditis via Inhibition of STAT3 Activation

Silencing IL12p35 Promotes Angiotensin II-Mediated Abdominal Aortic Aneurysm through Activating the STAT4 Pathway

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