Fibroblast cyclo-oxygenase-2 associated with the kidney restrains methylarginines and thrombosis: relevance to cardiovascular side effects of non-steroidal anti-inflammatory drugs
Author(s)
Type
Journal Article
Abstract
Use of non-steroidal anti-inflammatory drugs (NSAIDs), which work by inhibiting cyclo-oxygenase-2, is associated with an increased risk of thrombotic cardiovascular events. There is increasing evidence for a role of renal cyclo-oxygenase-2 in NSAID-induced cardiovascular side effects, including through dysregulation of methylarginines, endogenous inhibitors of nitric oxide synthase. However, delineating the significance of renal pathways has been hampered by a lack of suitable models. Here we have generated mouse models of cyclo-oxygenase-2 deficiency from relevant cell types to test directly their contributions. Deletion of cyclo-oxygenase-2 from fibroblasts reduced total renal expression without altering expression elsewhere. Fibroblast cyclo-oxygenase-2 knockout increased thrombosis after arterial injury, which was associated with the accumulation of plasma methylarginines and consequent systemic endothelial nitric oxide dysfunction. The pro-thrombotic phenotype in these animals was reversed by L-arginine, which competes against the inhibitory effect of methylarginines, in line with a mechanistic contribution. By comparison, pro-thrombotic phenotypes in endothelial cyclo-oxygenase-2 knockout mice, which occur via a vascular mechanism, were not associated with changes in methylarginines and were insensitive to L-arginine. Taken together, these studies provide direct evidence for a role of fibroblast and renal cyclo-oxygenase-2 in anti-thrombotic protection and demonstrate that to understand, predict, treat, and/or prevent NSAID-induced cardiovascular side effects, we must consider these pathways.
Graphical Abstract
Our findings from cell-specific mouse models suggest COX-2 in fibroblasts in the kidney regulate methylarginine pathways. When this is blocked, ADMA accumulates in the circulation to cause systemic nitric oxide synthase inhibition and resulting in increased in thrombotic tone. We propose this mechanism functions alongside vascular COX-2 and other pathways to explain how non-steroidal anti-inflammatory drugs increase risk of thrombotic events in humans.
Graphical Abstract
Our findings from cell-specific mouse models suggest COX-2 in fibroblasts in the kidney regulate methylarginine pathways. When this is blocked, ADMA accumulates in the circulation to cause systemic nitric oxide synthase inhibition and resulting in increased in thrombotic tone. We propose this mechanism functions alongside vascular COX-2 and other pathways to explain how non-steroidal anti-inflammatory drugs increase risk of thrombotic events in humans.
Date Issued
2025-08-31
Date Acceptance
2025-08-12
Citation
The FASEB Journal, 2025, 39 (16)
ISSN
0892-6638
Publisher
Wiley
Journal / Book Title
The FASEB Journal
Volume
39
Issue
16
Copyright Statement
© 2025 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Publication Status
Published
Article Number
70963
Date Publish Online
2025-08-28