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Inhibitors of gastric acid secretion increase oxidative stress and matrix metalloproteinase-2 activity leading to vascular remodeling

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Abstract

The use of inhibitors of gastric acid secretion (IGAS), especially proton pump inhibitors (PPI), has been associated with increased cardiovascular risk. While the mechanisms involved are not known, there is evidence supporting increased oxidative stress, a major activator of matrix metalloproteinases (MMP), as an important player in such effect. However, there is no study showing whether other IGAS such as histamine H2-receptor blockers (H2RB) cause similar effects. This study aimed at examining whether treatment with the H2RB ranitidine promotes oxidative stress resulting in vascular MMP activation and corresponding functional and structural alterations in the vasculature, as compared with those found with the PPI omeprazole. Male Wistar rats were treated (4 weeks) with vehicle (2% tween 20), omeprazole (10 mg/Kg/day; i.p.) or ranitidine (100 mg/Kg/day; gavage). Then the aorta was collected to perform functional, biochemical, and morphometric analysis. Both ranitidine and omeprazole increased gastric pH and oxidative stress assessed in situ with the fluorescent dye dihydroethidium (DHE) and with lucigenin chemiluminescence assay. Both IGAS augmented vascular activated MMP-2. These findings were associated with aortic remodeling (increased media/lumen ratio and number of cells/μm2). Both IGAS also impaired the endothelium-dependent relaxation induced by acetylcholine (isolated aortic ring preparation). This study provides evidence that the H2RB ranitidine induces vascular dysfunction, redox alterations, and remodeling similar to those found with the PPI omeprazole. These findings strongly suggest that IGAS increase oxidative stress and matrix metalloproteinase-2 activity leading to vascular remodeling, which helps to explain the increased cardiovascular risk associated with the use of those drugs.

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Funding

This work was supported by Fundação de Aparo a Pesquisa do Estado de São Paulo (FAPESP Grant number 2014–23946-0), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq - Grant number 406442/2022-3) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.

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Authors and Affiliations

  1. Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, 14049-900, Brazil

    Renato C. Nogueira, Jéssica M. Sanches-lopes, Gustavo H. Oliveira-Paula & Jose E. Tanus-Santos

  2. Division of Cardiology, Department of Medicine, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA

    Gustavo H. Oliveira-Paula

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  1. Renato C. Nogueira
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RCN and JMS-L: Contributed equally to this article in Conceptualization, Data curation, Formal analysis, Methodology, Writing. [GHO-P]: Conceptualization, Data curation, Formal analysis, Methodology, Writing. JET-S: Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Writing. All authors read and approved the final version of the manuscript.

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Correspondence to Jose E. Tanus-Santos.

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The present study and experimental procedures complied with the ARRIVE guidelines and were in accordance with the National Research Council's Guide for the Care and Use of Laboratory Animals. The study was approved by the Animal Care and Use Committee of Ribeirao Preto Medical School—University of Sao Paulo (protocol code 171–2016).

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Nogueira, R.C., Sanches-lopes, J.M., Oliveira-Paula, G.H. et al. Inhibitors of gastric acid secretion increase oxidative stress and matrix metalloproteinase-2 activity leading to vascular remodeling. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-023-04921-x

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