Cyclooxygenase-2 selectively controls renal blood flow through a novel pparβ/δ-dependent vasodilator pathway
Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by nonsteroidal anti-inflammatory drugs. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive COX-2 e...
| Main Authors: | , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2018
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/89772 http://hdl.handle.net/10220/46357 |
| _version_ | 1826110220436242432 |
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| author | Shala, Fisnik Nair, Anitha S. Ahmetaj-Shala, Blerina Jiao, Jing Kirkby, Nicholas S. Sampaio, Walkyria Etelvino, Gisele Alves, Daniele T. Anders, Katie L. Temponi, Rafael Herschman, Harvey R. Wang, Xiaomeng Wahli, Walter Santos, Robson A. Mitchell, Jane A. |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Shala, Fisnik Nair, Anitha S. Ahmetaj-Shala, Blerina Jiao, Jing Kirkby, Nicholas S. Sampaio, Walkyria Etelvino, Gisele Alves, Daniele T. Anders, Katie L. Temponi, Rafael Herschman, Harvey R. Wang, Xiaomeng Wahli, Walter Santos, Robson A. Mitchell, Jane A. |
| author_sort | Shala, Fisnik |
| collection | NTU |
| description | Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by nonsteroidal anti-inflammatory drugs. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive COX-2 expression in the kidney regulates renal function and blood flow; however, the global relevance of the kidney versus other tissues to COX-2–dependent blood flow regulation is not known. Here, we used a microsphere deposition technique and pharmacological COX-2 inhibition to map the contribution of COX-2 to regional blood flow in mice and compared this to COX-2 expression patterns using luciferase reporter mice. Across all tissues studied, COX-2 inhibition altered blood flow predominantly in the kidney, with some effects also seen in the spleen, adipose, and testes. Of these sites, only the kidney displayed appreciable local COX-2 expression. As the main site where COX-2 regulates blood flow, we next analyzed the pathways involved in kidney vascular responses using a novel technique of video imaging small arteries in living tissue slices. We found that the protective effect of COX-2 on renal vascular function was associated with prostacyclin signaling through PPARβ/δ (peroxisome proliferator-activated receptor-β/δ). These data demonstrate the kidney as the principle site in the body where local COX-2 controls blood flow and identifies a previously unreported PPARβ/δ-mediated renal vasodilator pathway as the mechanism. These findings have direct relevance to the renal and cardiovascular side effects of drugs that inhibit COX-2, as well as the potential of the COX-2/prostacyclin/PPARβ/δ axis as a therapeutic target in renal disease. |
| first_indexed | 2024-10-01T02:30:50Z |
| format | Journal Article |
| id | ntu-10356/89772 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:30:50Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/897722020-11-01T05:10:45Z Cyclooxygenase-2 selectively controls renal blood flow through a novel pparβ/δ-dependent vasodilator pathway Shala, Fisnik Nair, Anitha S. Ahmetaj-Shala, Blerina Jiao, Jing Kirkby, Nicholas S. Sampaio, Walkyria Etelvino, Gisele Alves, Daniele T. Anders, Katie L. Temponi, Rafael Herschman, Harvey R. Wang, Xiaomeng Wahli, Walter Santos, Robson A. Mitchell, Jane A. Lee Kong Chian School of Medicine (LKCMedicine) Endothelium Cyclooxygenase 2 DRNTU::Science::Medicine Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by nonsteroidal anti-inflammatory drugs. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive COX-2 expression in the kidney regulates renal function and blood flow; however, the global relevance of the kidney versus other tissues to COX-2–dependent blood flow regulation is not known. Here, we used a microsphere deposition technique and pharmacological COX-2 inhibition to map the contribution of COX-2 to regional blood flow in mice and compared this to COX-2 expression patterns using luciferase reporter mice. Across all tissues studied, COX-2 inhibition altered blood flow predominantly in the kidney, with some effects also seen in the spleen, adipose, and testes. Of these sites, only the kidney displayed appreciable local COX-2 expression. As the main site where COX-2 regulates blood flow, we next analyzed the pathways involved in kidney vascular responses using a novel technique of video imaging small arteries in living tissue slices. We found that the protective effect of COX-2 on renal vascular function was associated with prostacyclin signaling through PPARβ/δ (peroxisome proliferator-activated receptor-β/δ). These data demonstrate the kidney as the principle site in the body where local COX-2 controls blood flow and identifies a previously unreported PPARβ/δ-mediated renal vasodilator pathway as the mechanism. These findings have direct relevance to the renal and cardiovascular side effects of drugs that inhibit COX-2, as well as the potential of the COX-2/prostacyclin/PPARβ/δ axis as a therapeutic target in renal disease. MOE (Min. of Education, S’pore) Published version 2018-10-18T04:26:22Z 2019-12-06T17:33:08Z 2018-10-18T04:26:22Z 2019-12-06T17:33:08Z 2018 Journal Article Kirkby, N. S., Sampaio, W., Etelvino, G., Alves, D. T., Anders, K. L., Temponi, R., . . . Mitchell, J. A. (2018). Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARβ/δ-Dependent Vasodilator Pathway. Hypertension, 71(2), 297-305. doi:10.1161/HYPERTENSIONAHA.117.09906 0194-911X https://hdl.handle.net/10356/89772 http://hdl.handle.net/10220/46357 10.1161/HYPERTENSIONAHA.117.09906 en Hypertension © 2018 The Authors. Hypertension is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. 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 that the original work is properly cited. 9 p. application/pdf |
| spellingShingle | Endothelium Cyclooxygenase 2 DRNTU::Science::Medicine Shala, Fisnik Nair, Anitha S. Ahmetaj-Shala, Blerina Jiao, Jing Kirkby, Nicholas S. Sampaio, Walkyria Etelvino, Gisele Alves, Daniele T. Anders, Katie L. Temponi, Rafael Herschman, Harvey R. Wang, Xiaomeng Wahli, Walter Santos, Robson A. Mitchell, Jane A. Cyclooxygenase-2 selectively controls renal blood flow through a novel pparβ/δ-dependent vasodilator pathway |
| title | Cyclooxygenase-2 selectively controls renal blood flow through a novel pparβ/δ-dependent vasodilator pathway |
| title_full | Cyclooxygenase-2 selectively controls renal blood flow through a novel pparβ/δ-dependent vasodilator pathway |
| title_fullStr | Cyclooxygenase-2 selectively controls renal blood flow through a novel pparβ/δ-dependent vasodilator pathway |
| title_full_unstemmed | Cyclooxygenase-2 selectively controls renal blood flow through a novel pparβ/δ-dependent vasodilator pathway |
| title_short | Cyclooxygenase-2 selectively controls renal blood flow through a novel pparβ/δ-dependent vasodilator pathway |
| title_sort | cyclooxygenase 2 selectively controls renal blood flow through a novel pparβ δ dependent vasodilator pathway |
| topic | Endothelium Cyclooxygenase 2 DRNTU::Science::Medicine |
| url | https://hdl.handle.net/10356/89772 http://hdl.handle.net/10220/46357 |
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