Omeprazole induces vascular remodeling by mechanisms involving xanthine oxidoreductase and matrix metalloproteinase activation
Copyright © 2021 Elsevier Inc. All rights reserved..
Proton pump inhibitors (PPI) are commonly used drugs that may increase the cardiovascular risk by mechanisms not entirely known. We examined whether the PPI omeprazole promotes vascular oxidative stress mediated by xanthine oxidoreductase (XOR) leading to activation of matrix metalloproteinases (MMPs) and vascular remodeling. We studied Wistar rats treated with omeprazole (or vehicle) combined with the XOR inhibitor allopurinol (or vehicle) for four weeks. Systolic blood pressure (SBP) measured by tail-cuff plethysmography was not affected by treatments. Omeprazole treatment increased the aortic cross-sectional area and media/lumen ratio by 25% (P < 0.05). Omeprazole treatment decreased gastric pH and induced vascular remodeling accompanied by impaired endothelium-dependent aortic responses (assessed with isolated aortic ring preparation) to acetylcholine (P < 0.05). Omeprazole increased vascular active MMP-2 expression and activity assessed by gel zymography and in situ zymography, respectively (P < 0.05). Moreover, omeprazole enhanced vascular oxidative stress assessed in situ with the fluorescent dye DHE and with the lucigenin chemiluminescence assay (both P < 0.05). All these biochemical changes caused by omeprazole were associated with increased vascular XOR activity (but not XOR expression assessed by Western blot) and treatment with allopurinol fully prevented them (all P < 0.05). Importantly, treatment with allopurinol prevented the vascular dysfunction and remodeling caused by omeprazole. Our results suggest that the long-term use of omeprazole induces vascular dysfunction and remodeling by promoting XOR-derived reactive oxygen species formation and MMP activation. These findings provide evidence of a new mechanism that may underlie the unfavorable cardiovascular outcomes observed with PPI therapy. Clinical studies are warranted to validate our findings.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:190 |
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| Enthalten in: |
Biochemical pharmacology - 190(2021) vom: 25. Aug., Seite 114633 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nogueira, Renato C [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.11.2021 Date Revised 17.11.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bcp.2021.114633 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Omeprazole induces vascular remodeling by mechanisms involving xanthine oxidoreductase and matrix metalloproteinase activation |
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| 520 | |a Copyright © 2021 Elsevier Inc. All rights reserved. | ||
| 520 | |a Proton pump inhibitors (PPI) are commonly used drugs that may increase the cardiovascular risk by mechanisms not entirely known. We examined whether the PPI omeprazole promotes vascular oxidative stress mediated by xanthine oxidoreductase (XOR) leading to activation of matrix metalloproteinases (MMPs) and vascular remodeling. We studied Wistar rats treated with omeprazole (or vehicle) combined with the XOR inhibitor allopurinol (or vehicle) for four weeks. Systolic blood pressure (SBP) measured by tail-cuff plethysmography was not affected by treatments. Omeprazole treatment increased the aortic cross-sectional area and media/lumen ratio by 25% (P < 0.05). Omeprazole treatment decreased gastric pH and induced vascular remodeling accompanied by impaired endothelium-dependent aortic responses (assessed with isolated aortic ring preparation) to acetylcholine (P < 0.05). Omeprazole increased vascular active MMP-2 expression and activity assessed by gel zymography and in situ zymography, respectively (P < 0.05). Moreover, omeprazole enhanced vascular oxidative stress assessed in situ with the fluorescent dye DHE and with the lucigenin chemiluminescence assay (both P < 0.05). All these biochemical changes caused by omeprazole were associated with increased vascular XOR activity (but not XOR expression assessed by Western blot) and treatment with allopurinol fully prevented them (all P < 0.05). Importantly, treatment with allopurinol prevented the vascular dysfunction and remodeling caused by omeprazole. Our results suggest that the long-term use of omeprazole induces vascular dysfunction and remodeling by promoting XOR-derived reactive oxygen species formation and MMP activation. These findings provide evidence of a new mechanism that may underlie the unfavorable cardiovascular outcomes observed with PPI therapy. Clinical studies are warranted to validate our findings | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a MMP-2 | |
| 650 | 4 | |a Omeprazole | |
| 650 | 4 | |a Vascular remodeling | |
| 650 | 4 | |a Xanthine oxidoreductase | |
| 650 | 7 | |a Anti-Ulcer Agents |2 NLM | |
| 650 | 7 | |a Enzyme Inhibitors |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
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| 650 | 7 | |a Xanthine Dehydrogenase |2 NLM | |
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| 650 | 7 | |a Matrix Metalloproteinases |2 NLM | |
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| 650 | 7 | |a Omeprazole |2 NLM | |
| 650 | 7 | |a KG60484QX9 |2 NLM | |
| 700 | 1 | |a Pinheiro, Lucas C |e verfasserin |4 aut | |
| 700 | 1 | |a Sanches-Lopes, Jessica M |e verfasserin |4 aut | |
| 700 | 1 | |a Parente, Juliana M |e verfasserin |4 aut | |
| 700 | 1 | |a Oliveira-Paula, Gustavo H |e verfasserin |4 aut | |
| 700 | 1 | |a Conde, Sandra O |e verfasserin |4 aut | |
| 700 | 1 | |a Castro, Michele M |e verfasserin |4 aut | |
| 700 | 1 | |a Tanus-Santos, Jose E |e verfasserin |4 aut | |
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