A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model.

Authors

Lauren M Weaver, University of Kentucky
Madeline J Stewart, University of Kentucky
Kai Ding, University of KentuckyFollow
Charles D. Loftin, University of KentuckyFollow
Fang Zheng, University of Kentucky
Chang-Guo Zhan, University of KentuckyFollow

Abstract

Abdominal aortic aneurysm (AAA) is a deadly, permanent ballooning of the aortic artery. Pharmacological and genetic studies have pointed to multiple proteins, including microsomal prostaglandin E₂ synthase-1 (mPGES-1), as potentially promising targets. However, it remains unknown whether administration of an mPGES-1 inhibitor can effectively attenuate AAA progression in animal models. There are still no FDA-approved pharmacological treatments for AAA. Current research stresses the importance of both anti-inflammatory drug targets and rigor of translatability. Notably, mPGES-1 is an inducible enzyme responsible for overproduction of prostaglandin E₂ (PGE₂)-a well-known principal pro-inflammatory prostanoid. Here we demonstrate for the first time that a highly selective mPGES-1 inhibitor (UK4b) can completely block further growth of AAA in the ApoE-/- angiotensin (Ang)II mouse model. Our findings show promise for the use of a mPGES-1 inhibitor like UK4b as interventional treatment of AAA and its potential translation into the clinical setting.

Document Type

Article

Publication Date

3-23-2024

Notes/Citation Information

© The Author(s) 2024

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41598-024-57437-9

Funding Information

This work was supported in part by funding from the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy, the Investigator-Initiated Research Award W81XWH2211000 (to Dr. Chang-Guo Zhan and Dr. Fang Zheng) from the U.S. Department of Defense (DoD) Chronic Pain Management Research Program (CPMRP), and an award (to Dr. Fang Zheng and Dr. Chang-Guo Zhan) from the Kentucky Network for Innovation & Commercialization (KYNETIC) program associated with NIH Grant U01 HL152392 (funded by NCI, NEI, NHGRI, NIDCR, the Commonwealth of Kentucky). Funding was also provided as support from the Pharmaceutical Sciences Excellence in Graduate Achievement Fellowship from the University of Kentucky College of Pharmacy and the Centers of Biomedical Research Excellence (COBRE) Research Cores supported by the National Institutes of Health (P20 GM130456 and P30 GM127211).

Repository Citation

Weaver, Lauren M; Stewart, Madeline J; Ding, Kai; Loftin, Charles D.; Zheng, Fang; and Zhan, Chang-Guo, "A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model." (2024). Pharmaceutical Sciences Faculty Publications. 208.
https://uknowledge.uky.edu/ps_facpub/208