Studies on anti-inflammatory and vasoactive effects of mPGES-1 inhibition

Inflammation is the basis for various serious illnesses such as rheumatic diseases, cardiovascular diseases, and cancer. Prostaglandin E2 (PGE2) is a pro-inflammatory lipid mediator produced by cyclooxygenases (COX1/2) and the microsomal prostaglandin E synthase 1 (mPGES-1). Nonsteroidal anti-inflammatory drugs (NSAIDS) targeting COX successfully reduce pain and inflammation. However, gastrointestinal and cardiovascular side effects associated with blockade of all prostaglandins limit their use. Selective inhibition of mPGES-1 is an alternative therapeutic strategy to impede PGE2 production while sparing or even upregulating other lipid mediators. When and where the shunting of PGH2 to other prostanoids occurs and whether it interferes with or contributes to the therapeutic effects of mPGES-1 inhibition is not fully understood. The overall aim of this thesis was to study the anti-inflammatory and vasoactive effects of mPGES-1 inhibition in models of inflammation and cardiovascular disease and to investigate the possible shunting of PGH2 to PGD2 and PGI2. The methodological approach was principally based on liquid chromatography-tandem mass spectrometry, biochemical assays as well as wire-myography.

In Paper I five new mPGES-1 inhibitors were characterized. The inhibitors selectively suppressed PGE2 formation in in-vitro and in-vivo assays, reduced acute paw swelling in rats, and reduced adrenergic vasoconstriction. The results of this study serve as a basis for the application of these inhibitors in pre-clinical research. Depletion of mPGES-1 may lead to the re-direction of PGH2 into the PGD2/15-deoxy-Δ12,14-PGJ2 (15dPGJ2) pathway, which has been described to be anti-inflammatory and pro-resolving. In Paper II, we studied the biosynthesis and metabolism of 15dPGJ2 via conjugation to glutathione in immune cells and upon inhibition of mPGES-1. The results of this study demonstrate the formation of 15dPGJ2-glutathione and 15dPGJ2-cysteine conjugates in immune cells, the involvement of MGST3 in this pathway and the preservation of the PGD2/15dPGJ2 pathway upon inhibition of mPGES-1. Another important aspect of mPGES-1 inhibition is the redirection of excess PGH2 into the PGI2 pathway. A decrease in PGI2 levels as a result of COX-2 inhibition has been associated with increased cardiovascular risk in patients treated with selective NSAIDs. In Paper III we aimed to study the effects of mPGES-1 inhibition on human resistance arteries. Inhibition of mPGES- 1 significantly reduced adrenergic vasoconstriction and enhanced relaxation. Our results suggest that multiple pathways in addition to shunting to PGI2 may be involved in the vasoactive effects of mPGES-1 inhibition in human microcirculation. In Paper IV we studied the effects of mPGES-1 inhibition in a mouse model of MI. The results of this study indicate that pharmacological inhibition of mPGES-1 could improve cardiac function after MI and increase the PGI2/PGE2 metabolite ratio in urine compared with controls.

The results from this thesis contribute to a better understanding of the mechanisms underlying the effects seen after inhibition of mPGES-1 in models of inflammation and cardiovascular disease.

List of scientific papers

I. Biological characterization of new mPGES-1 inhibitors in pre-clinical models of inflammation and vascular tone. Karin Larsson*, Julia Steinmetz*, Filip Bergqvist*, Samsul Arefin, Linda Spahiu, Johan Wannberg, Sven-Christian Pawelzik, Ralf Morgenstern, Patric Stenberg, Karolina Kublickiene, Marina Korotkova, Per-Johan Jakobsson. British Journal of pharmacology. 2019;176(24):4625-4638. *Equal author contribution.
https://doi.org/10.1111/bph.14827

II. Biosynthesis of prostaglandin 15dPGJ2-glutathione and -cysteine conjugates in macrophages and mast cells via MGST3. Julia Steinmetz-Späh, Jianyang Liu, Rajkumar Singh, Maria Ekoff, Sanjaykumar Boddul, Xiao Tang, Filip Bergqvist, Helena Idborg, Pascal Heitel, Elin Rönnberg, Daniel Merk, Fredrik Wermeling, Jesper Z. Haeggström, Gunnar Nilsson, Dieter Steinhilber, Karin Larsson, Marina Korotkova, Per-Johan Jakobsson. Journal of Lipid Research. 2022. [Accepted]
https://doi.org/10.1016/j.jlr.2022.100310

III. Effects of microsomal prostaglandin E synthase-1 (MPGES-1) inhibition on resistance artery tone in patients with end stage kidney disease. Julia Steinmetz-Späh*, Samsul Arefin*, Karin Larsson, Jabin Jahan, Neja Mudrovcic, Lars Wennberg, Peter Stenvinkel, Marina Korotkova, Karolina Kublickiene*, Per-Johan Jakobsson*. British Journal of Pharmacology. 2022;179(7):1433-1449. *Equal author contribution.
https://doi.org/10.1111/bph.15729

IV. Microsomal prostaglandin E synthase-1 inhibition protects cardiac remodeling after myocardial infarction in mice. Yuze Zhang*, Julia Steinmetz-Späh*, Helena Idborg, Liyuan Zhu, Huihui Li, Haojie Rao, Zengrong Chen, Ziyi Guo, Lejia Hu, Chuansheng Xu, Hong Chen, Marina Korotkova, Per-Johan Jakobsson*, Miao Wang*. *Equal author contribution. [Submitted]