Protein Never in Mitosis Gene A Interacting-1 regulates calpain activity and the degradation of cyclooxygenase-2 in endothelial cells
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Background: The peptidyl-proline isomerase, Protein Never in Mitosis Gene A Interacting-1 (PIN1), regulates turnover of inducible nitric oxide synthase (iNOS) in murine aortic endothelial cells (MAEC) stimulated with E. coli endotoxin (LPS) and interferon-γ (IFN). Degradation of iNOS was reduced by a calpain inhibitor, suggesting that PIN1 may affect induction of other calpain-sensitive inflammatory proteins, such as cyclooxygenase (COX)-2, in MAEC. Methods: MAEC, transduced with lentivirus encoding an inactive control short hairpin (sh) RNA or one targeting PIN1 that reduced PIN1 by 85%, were used. Cells were treated with LPS/IFN, calpain inhibitors (carbobenzoxy-valinyl-phenylalaninal (zVF), PD150606), cycloheximide and COX inhibitors to determine the effect of PIN1 depletion on COX-2 and calpain. Results: LPS or IFN alone did not induce COX-2. However, treatment with 10 μg LPS plus 20 ng IFN per ml induced COX-2 protein 10-fold in Control shRNA MAEC. Induction was significantly greater (47-fold) in PIN1 shRNA cells. COX-2-dependent prostaglandin E2 production increased 3-fold in KD MAEC, but did not increase in Control cells. The additional increase in COX-2 protein due to PIN1 depletion was post-transcriptional, as induction of COX-2 mRNA by LPS/IFN was the same in cells containing or lacking PIN1. Instead, the loss of COX-2 protein, after treatment with cycloheximide to block protein synthesis, was reduced in cells lacking PIN1 in comparison with Control cells, indicating that degradation of the enzyme was reduced. zVF and PD150606 each enhanced the induction of COX-2 by LPS/IFN. zVF also slowed the loss of COX-2 after treatment with cycloheximide, and COX-2 was degraded by exogenous μ-calpain in vitro. In contrast to iNOS, physical interaction between COX-2 and PIN1 was not detected, suggesting that effects of PIN1 on calpain, rather than COX-2 itself, affect COX-2 degradation. While cathepsin activity was unaltered, depletion of PIN1 reduced calpain activity by 55% in comparison with Control shRNA cells. Conclusion: PIN1 reduced calpain activity and slowed the degradation of COX-2 in MAEC, an effect recapitulated by an inhibitor of calpain. Given the sensitivity of COX-2 and iNOS to calpain, PIN1 may normally limit induction of these and other calpain substrates by maintaining calpain activity in endothelial cells.
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Pin1 prevents the production of prostaglandin E2 in MAEC by regulating the degradation of cyclooxygenase-2 induced by LPS.
“Pin1 prevents the production of prostaglandin E2 in MAEC by regulating the degradation of cyclooxygenase-2 induced by LPS [9].”
From Prolyl Isomerase Pin1 Protects Mice from Endotoxin Shock (2011) · cites this paper as [9]
The Results (page unavailable) report that PIN1 knockdown increased COX-2–mediated prostaglandin E2 production in MAEC, and the Discussion links PIN1 to COX-2 degradation. The claim omits a decisive condition: the cells were treated with LPS plus IFN; the Results say LPS alone did not induce COX-2. The paper supports PIN1 restraining, rather than categorically preventing, this response. (LLM, conf=0.89)
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- Authors
- Liu, T., Schneider, R. A., Shah, V., Huang, Y., Likhotvorik, R. I., Keshvara, L., & Hoyt, D. G.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Hoyt, Dale G
- Venue
- Journal of Inflammation
- Published
- 2009-06-22
- Volume
- 6
- Issue
- 1
- Pages
- 20-20
- ISSN
- 1476-9255 (ISSN-L)
- PMC
- PMC2708161
- OpenAlex
- W2172176302
- Cited by
- 13
- References
- 44
- Citations by year
- 2024: 2 · 2023: 1 · 2021: 1 · 2018: 1 · 2016: 1 · 2014: 3
- FWCI
- 0.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Inflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Ohio State University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- Pin1, peptidyl-prolyl isomerase, calpain, cyclooxygenase-2, protein degradation, endothelial cells, lipopolysaccharide, interferon-gamma, prostaglandin E2, post-transcriptional regulation, calpain-1, inflammatory cytokines, aortic endothelium, shRNA knockdown, z-VAD-fmk
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