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

Lauren M. Weaver; Madeline J. Stewart; Kai Ding; Charles D. Loftin; Fang Zheng; Chang Guo Zhan

doi:10.1038/s41598-024-57437-9

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

Lauren M. Weaver, Madeline J. Stewart, Kai Ding, Charles D. Loftin, Fang Zheng, Chang Guo Zhan

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Article number	6959
Journal	Scientific Reports
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41598-024-57437-9
State	Published - Dec 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

The authors would like to thank the Molecular Modeling and Biopharmaceutical Center (MMBC), Center for Pharmaceutical Research and Innovation (CPRI), Saha Cardiovascular Center, Imaging Core Facility, Tissue Histology Core Facility, and Division of Laboratory Animal Resources at the University of Kentucky for using their facilities. 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).

Funders	Funder number
Division of Laboratory Medicine
Center for Pharmaceutical Research and Innovation, University of Kentucky
National Institute of GeneralMedical Sciences Centers of Biomedical Research Excellence
National Human Genome Research Institute
National Childhood Cancer Registry – National Cancer Institute
Molecular Modeling and Biopharmaceutical Center
Kentucky Network for Innovation & Commercialization
National Eye Institute (NEI)
Saha Cardiovascular Research Center and Saha Aortic Center
National Institute of Dental and Craniofacial Research
U.S. Department of Defense
University of Kentucky College of Pharmacy	W81XWH2211000
National Institutes of Health (NIH)	P30 GM127211, P20 GM130456, U01 HL152392

Keywords

Abdominal aortic aneurysm
Aneurysm
Anti-inflammation
Prostaglandin E2
mPGES-1 inhibitor

ASJC Scopus subject areas

General

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10.1038/s41598-024-57437-9

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title = "A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model",

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.",

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AU - Zhan, Chang Guo

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

Abstract

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Keywords

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