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GSK2593074A blocks progression of existing abdominal aortic dilation

OBJECTIVE: Receptor interacting proteins kinase 1 and 3 (RIPK1 and RIPK3) have been shown to play essential roles in the pathogenesis of abdominal aortic aneurysms (AAAs) by mediating necroptosis and inflammation. We previously discovered a small molecular inhibitor GSK2593074A (GSK’074) that binds...

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Autores principales: Khoury, Mitri K., Zhou, Ting, Yang, Huan, Prince, Samantha R., Gupta, Kartik, Stranz, Amelia R., Wang, Qiwei, Liu, Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872141/
https://www.ncbi.nlm.nih.gov/pubmed/33569546
http://dx.doi.org/10.1016/j.jvssci.2020.07.001
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author Khoury, Mitri K.
Zhou, Ting
Yang, Huan
Prince, Samantha R.
Gupta, Kartik
Stranz, Amelia R.
Wang, Qiwei
Liu, Bo
author_facet Khoury, Mitri K.
Zhou, Ting
Yang, Huan
Prince, Samantha R.
Gupta, Kartik
Stranz, Amelia R.
Wang, Qiwei
Liu, Bo
author_sort Khoury, Mitri K.
collection PubMed
description OBJECTIVE: Receptor interacting proteins kinase 1 and 3 (RIPK1 and RIPK3) have been shown to play essential roles in the pathogenesis of abdominal aortic aneurysms (AAAs) by mediating necroptosis and inflammation. We previously discovered a small molecular inhibitor GSK2593074A (GSK’074) that binds to both RIPK1 and RIPK3 with high affinity and prevents AAA formation in mice. In this study, we evaluated whether GSK’074 can attenuate progression of existing AAA in the calcium phosphate model. METHODS: C57BL6/J mice were subjected to the calcium phosphate model of aortic aneurysm generation. Mice were treated with either GSK’074 (4.65 mg/kg/day) or dimethylsulfoxide (DMSO) controls starting 7 days after aneurysm induction. Aneurysm growth was monitored via ultrasound imaging every 7 days until harvest on day 28. Harvested aortas were examined via immunohistochemistry. The impact of GSK’074 on vascular smooth muscle cells and macrophages were evaluated via flow cytometry and transwell migration assay. RESULTS: At the onset of treatment, mice in both the control (DMSO) and GSK’074 groups showed similar degree of aneurysmal expansion. The weekly ultrasound imaging showed a steady aneurysm growth in DMSO-treated mice. The aneurysm growth was attenuated by GSK’074 treatment. At humane killing, GSK’074-treated mice had significantly reduced progression in aortic diameter from baseline as compared with the DMSO-treated mice (83.2% ± 13.1% [standard error of the mean] vs 157.2% ± 32.0% [standard error of the mean]; P < .01). In addition, the GSK’074-treated group demonstrated reduced macrophages (F4/80, CD206, MHCII), less gelatinase activity, a higher level of smooth muscle cell-specific myosin heavy chain, and better organized elastin fibers within the aortic walls compared with DMSO controls. In vitro, GSK’074 inhibited necroptosis in mouse aortic smooth muscle cells; whereas, it was able to prevent macrophage migration without affecting Il1b and Tnf expression. CONCLUSIONS: GSK’074 is able to attenuate aneurysm progression in the calcium phosphate model. The ability to inhibit both vascular smooth muscle cell necroptosis and macrophage migration makes GSK’074 an attractive drug candidate for pharmaceutical treatment of aortic aneurysms.
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spelling pubmed-78721412021-02-09 GSK2593074A blocks progression of existing abdominal aortic dilation Khoury, Mitri K. Zhou, Ting Yang, Huan Prince, Samantha R. Gupta, Kartik Stranz, Amelia R. Wang, Qiwei Liu, Bo JVS Vasc Sci Basic Reserch Study OBJECTIVE: Receptor interacting proteins kinase 1 and 3 (RIPK1 and RIPK3) have been shown to play essential roles in the pathogenesis of abdominal aortic aneurysms (AAAs) by mediating necroptosis and inflammation. We previously discovered a small molecular inhibitor GSK2593074A (GSK’074) that binds to both RIPK1 and RIPK3 with high affinity and prevents AAA formation in mice. In this study, we evaluated whether GSK’074 can attenuate progression of existing AAA in the calcium phosphate model. METHODS: C57BL6/J mice were subjected to the calcium phosphate model of aortic aneurysm generation. Mice were treated with either GSK’074 (4.65 mg/kg/day) or dimethylsulfoxide (DMSO) controls starting 7 days after aneurysm induction. Aneurysm growth was monitored via ultrasound imaging every 7 days until harvest on day 28. Harvested aortas were examined via immunohistochemistry. The impact of GSK’074 on vascular smooth muscle cells and macrophages were evaluated via flow cytometry and transwell migration assay. RESULTS: At the onset of treatment, mice in both the control (DMSO) and GSK’074 groups showed similar degree of aneurysmal expansion. The weekly ultrasound imaging showed a steady aneurysm growth in DMSO-treated mice. The aneurysm growth was attenuated by GSK’074 treatment. At humane killing, GSK’074-treated mice had significantly reduced progression in aortic diameter from baseline as compared with the DMSO-treated mice (83.2% ± 13.1% [standard error of the mean] vs 157.2% ± 32.0% [standard error of the mean]; P < .01). In addition, the GSK’074-treated group demonstrated reduced macrophages (F4/80, CD206, MHCII), less gelatinase activity, a higher level of smooth muscle cell-specific myosin heavy chain, and better organized elastin fibers within the aortic walls compared with DMSO controls. In vitro, GSK’074 inhibited necroptosis in mouse aortic smooth muscle cells; whereas, it was able to prevent macrophage migration without affecting Il1b and Tnf expression. CONCLUSIONS: GSK’074 is able to attenuate aneurysm progression in the calcium phosphate model. The ability to inhibit both vascular smooth muscle cell necroptosis and macrophage migration makes GSK’074 an attractive drug candidate for pharmaceutical treatment of aortic aneurysms. Elsevier 2020-07-28 /pmc/articles/PMC7872141/ /pubmed/33569546 http://dx.doi.org/10.1016/j.jvssci.2020.07.001 Text en © 2020 by the Society for Vascular Surgery. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Basic Reserch Study
Khoury, Mitri K.
Zhou, Ting
Yang, Huan
Prince, Samantha R.
Gupta, Kartik
Stranz, Amelia R.
Wang, Qiwei
Liu, Bo
GSK2593074A blocks progression of existing abdominal aortic dilation
title GSK2593074A blocks progression of existing abdominal aortic dilation
title_full GSK2593074A blocks progression of existing abdominal aortic dilation
title_fullStr GSK2593074A blocks progression of existing abdominal aortic dilation
title_full_unstemmed GSK2593074A blocks progression of existing abdominal aortic dilation
title_short GSK2593074A blocks progression of existing abdominal aortic dilation
title_sort gsk2593074a blocks progression of existing abdominal aortic dilation
topic Basic Reserch Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872141/
https://www.ncbi.nlm.nih.gov/pubmed/33569546
http://dx.doi.org/10.1016/j.jvssci.2020.07.001
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