GSK2593074A blocks progression of existing abdominal aortic dilation

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: 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. 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 mechan...

Vascular Smooth Muscle Cells in Aortic Aneurysm: From Genetics to Mechanisms

“… 86 , 87 Consistently, the dual inhibitor of RIP1/RIP3, GSK2593074A, inhibits angiotensin II– and calcium‐induced AAA in mice. 88 , 89 These studies reveal the potential application of necroptosis inhibitors in treating aortic aneurysm.…”

Gasdermin D Inhibitor Necrosulfonamide Alleviates Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice

“…NSA also reportedly inhibited necroptosis [ 52 , 57 ]. Pharmacologically inhibiting necroptosis with a small-molecule inhibitor (GSK2593074A) targeting receptor-interacting protein kinases 1 and 3 has been reported to attenuate experimental AAAs in an alternative AAA model [ 58 ]. Thus, we cannot rule out whether and to what extent the AAA suppression by NSA can be attributed to its effect on necroptosis.…”

The Role of RIPK1 and RIPK3 in Cardiovascular Disease

“…Khoury et al therefore sought to investigate the impact of GSK'074 treatment on aneurysm size after aneurysm formation. Using the CaCl 2 model of AAA, Khoury et al showed that treatment with GSK'074 from 7 to 28 days after aneurysm induction reduced aneurysm growth and inflammatory cell infiltrate while preserving native aortic elastin and smooth muscle cell structure [66]. Collectively, the findings of Wang, Zhou, and Khoury et al demonstrate that the necroptosis inhibitors Nec-1s and GSK'074 show clinical promise and should continue to be investigated in the context of AAA.…”