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Pharmacological Inhibition of Factor XIIa Attenuates Abdominal Aortic Aneurysm, Reduces Atherosclerosis, and Stabilizes Atherosclerotic Plaques
| Content Provider | Scilit |
|---|---|
| Author | Searle, Amy K. Chen, Yung-Chih Wallert, Maria Wang, Xiaowei Hosseini, Hamid Peter, Karlheinz McFadyen, James D. Maluenda, Ana C. Noonan, Jonathan Kanellakis, Peter Huang, Angela Lioe, Hadi Biondo, Mark Nolte, Marc W. Rossato, Paolo Bobik, Alex Panousis, Con |
| Editor | Zaldivia, Maria T. K. |
| Copyright Year | 2021 |
| Abstract | Background 3F7 is a monoclonal antibody targeting the enzymatic pocket of activated factor XII (FXIIa), thereby inhibiting its catalytic activity. Given the emerging role of FXIIa in promoting thromboinflammation, along with its apparent redundancy for hemostasis, the selective inhibition of FXIIa represents a novel and highly attractive approach targeting pathogenic processes that cause thromboinflammation-driven cardiovascular diseases. Methods The effects of FXIIa inhibition were investigated using three distinct mouse models of cardiovascular disease—angiotensin II-induced abdominal aortic aneurysm (AAA), an $ApoE^{−/−}$ model of atherosclerosis, and a tandem stenosis model of atherosclerotic plaque instability. 3F7 or its isotype control, BM4, was administered to mice (10 mg/kg) on alternate days for 4 to 8 weeks, depending on the experimental model. Mice were examined for the development and size of AAAs, or the burden and instability of atherosclerosis and associated markers of inflammation. Results Inhibition of FXIIa resulted in a reduced incidence of larger AAAs, with less acute aortic ruptures and an associated fibro-protective phenotype. FXIIa inhibition also decreased stable atherosclerotic plaque burden and achieved plaque stabilization associated with increased deposition of fibrous structures, a >2-fold thicker fibrous cap, increased cap-to-core ratio, and reduction in localized and systemic inflammatory markers. Conclusion Inhibition of FXIIa attenuates disease severity across three mouse models of thromboinflammation-driven cardiovascular diseases. Specifically, the FXIIa-inhibiting monoclonal antibody 3F7 reduces AAA severity, inhibits the development of atherosclerosis, and stabilizes vulnerable plaques. Ultimately, clinical trials in patients with cardiovascular diseases such as AAA and atherosclerosis are warranted to demonstrate the therapeutic potential of FXIIa inhibition. Y.-C.C., C.P., X.W., H.H., and K.P. designed the study. A.K.S., Y.-C.C., M.W., J.D.M., A.C.M., J.N., P.K., M.T.K.Z., A.H., H.L., M.B., M.W.N., P.R., X.W., and H.H. were involved in the acquisition and interpretation or analysis of data. A.K.S. drafted the manuscript. Y.-C.C., M.W., J.D.M., J.N., A.B., C.P., X.W., and K.P. provided critical review of the intellectual content of the manuscript. All authors approved the final version of the manuscript prior to submission.$ ^{*}$ Equally contributing first authors.$ ^{**}$ Equally contributing senior authors. Received: 30 April 2021 Accepted: 04 October 2021 Accepted Manuscript online: 07 October 2021 Article published online: 21 January 2022 © 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany |
| Related Links | http://www.thieme-connect.de/products/ejournals/pdf/10.1055/a-1663-8208.pdf |
| Ending Page | 207 |
| Page Count | 12 |
| Starting Page | 196 |
| ISSN | 2567689X |
| DOI | 10.1055/a-1663-8208 |
| Journal | Thrombosis and Haemostasis |
| Issue Number | 02 |
| Volume Number | 122 |
| Language | English |
| Publisher | Georg Thieme Verlag KG |
| Publisher Date | 2021-10-07 |
| Access Restriction | Open |
| Subject Keyword | Journal: Thrombosis and Haemostasis Peripheral Vascular Disease 3f7 Monoclonal Antibody Abdominal Aortic Aneurysm Coagulation Factor Xii Vulnerable Plaques |
| Content Type | Text |
| Resource Type | Article |
| Subject | Hematology |
