Year: 2020
Type: article
Abstract: 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: 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. CLINICAL RELEVANCE: Previous clinical trials evaluating pharmaceutical treatments in blocking aneurysm progression have failed. However, most agents used in those trials focused on inhibiting only one mechanism that contributes to aneurysm pathogenesis. In this study, we found GSK'074 is able to attenuate aneurysm progression in the calcium phosphate model by inhibiting both vascular smooth muscle cell necroptosis and macrophage migration, which are both key processes in the pathogenesis of aneurysm progression. The ability of GSK'0474 to inhibit multiple key pathologic mechanisms makes it an attractive therapeutic candidate for aneurysm progression.
Source: JVS Vascular Science
Institution: University of Wisconsin–Madison
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,800
Awards: Role of RIP3-laden extracellular vesicles in thrombosis and aortic aneurysm, Molecular Mechanisms in Abdominal Aortic Aneuysm, Ultrasonic and Photoacoustic Imaging System for Cancer & Cardiovascular Research, G1880183074, Stress keratin 17 and CD4/8 ratio as prognostic markers in HIV-related anogenital squamous cell precancers and cancers (Biospecimens/Biocohort), Necroptosis in abdominal aortic aneurysm: signaling mechanism and therapeutic targeting, G2434268055, G409125952, G42679306, G5480275804, Vascular smooth muscle cell apoptosis in intimal hyperplasia, G570748071, PKCd mediated serine phosphorylation of STAT3 worsens abdominal aortic aneurysm by enhancing RIP3 expression & necrosis, G625014357, G9000021186, G9000041265, G9000201687, G9000246156, G9000265189, G9000352744
OpenAlex ID: W3044729673