Omeprazole induces vascular remodeling by mechanisms involving xanthine oxidoreductase and matrix metalloproteinase activation

Nogueira, Renato C.; Pinheiro, Lucas C.; Sanches-Lopes, Jessica M.; Parente, Juliana Montenegro; Oliveira-Paula, Gustavo H.; Conde, Sandra O.; Castro, Michele M.; Tanus‐Santos, José Eduardo

doi:10.1016/j.bcp.2021.114633

Cited by 9 publications

(8 citation statements)

References 54 publications

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“…As indicated above, ALO has a direct intrinsic scavenger effect on ROS, regardless of its XOR activity inhibition 68–70 . When we tested this possibility in freshly dissected MFS ascending aortic rings measuring ROS production (H 2 O 2 ), where local aerobic and pH conditions in vivo favor XOR for H 2 O 2 production, ALO prevented its overproduction.…”

Section: Discussionmentioning

confidence: 85%

Allopurinol Blocks Aortic Aneurysm in a Mouse Model of Marfan Syndrome via Reducing Aortic Oxidative Stress

Rodriguez-Rovira

Arce

Rycke

et al. 2021

Preprint

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The pathogenesis and progression of aortic aneurysm in Marfan syndrome (MFS) involves dysregulated TGF-β and nitric oxide signaling, altered hemodynamics, and biomechanical forces. Increasing evidence indicates that redox stress participates in MFS aortopathy development, though its contribution is not well established. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS mice and in patient aortic samples. Here we address the contribution of xanthine dehydrogenase (XDH) which catabolizes purines into uric acid plus ROS. XDH mRNA and protein expression levels are increased in the aorta of young but not older MFS mice (Fbn1C1041G/+). The protein and enzymatic activity of the oxidase form (XO) is increased with respect to the dehydrogenase. In patients, XO protein levels were increased in the dilated and the adjacent non-dilated zone of aortic aneurysm. The palliative administration of the XDH inhibitor allopurinol attenuated the progression of the aortic root aneurysm in MFS mice. Allopurinol was also protective when administrated before the appearance of aneurysm onset. MFS-induced elastic fiber fragmentation, fibrotic remodeling, nuclear translocation of pNRF2, and increased 3-nitrotyrosine levels in the aortic tunica media, as well as endothelial dysfunction, were all prevented by allopurinol. Mechanistically, allopurinol mediates these effects by inhibiting H2O2 overproduction, with no apparent relevance for uric acid, whose plasma levels remained constant with age. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and supports a clinical trial for allopurinol in the pharmacological treatment of MFS aortopathy.

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Section: Discussionmentioning

confidence: 85%

Allopurinol Blocks Aortic Aneurysm in a Mouse Model of Marfan Syndrome via Reducing Aortic Oxidative Stress

Rodriguez-Rovira

Arce

Rycke

et al. 2021

Preprint

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“…The mechanism for this association is not completely elucidated but experimental evidence suggested that the use of PPI may influence metalloproteinase (MMP) activity. In particular, omeprazole induced vascular MMP-2 expression and activity, resulting in increased media thickness and vascular oxidative stress [29].…”

Section: Discussionmentioning

confidence: 99%

Association of proprotein convertase subtilisin/kexin type 9 (PCSK9) levels with abnormally high ankle-brachial index in atrial fibrillation

et al. 2023

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Background: High ankle-brachial index (ABI) has been associated with increased risk of worse outcomes in the general population. Few data on atrial fibrillation (AF) exist. Experimental data suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) contributes to vascular calcification but clinical data on this association are lacking. Aims:We wanted to investigate the relationship between circulating PCSK9 levels and an abnormally high ABI in patients suffering from AF. Methods:We analyzed data from 579 patients included in the prospective ATHERO-AF study. An ABI≥1.4 was considered high. PCSK9 levels were measured coincidentally with ABI measurement. We used optimized cut-offs of PCSK9 for both ABI and mortality obtained from Receiver Operator Characteristic (ROC) curve analysis. All-cause mortality according to the ABI value was also analyzed.Results: One hundred and fifteen patients (19.9%) had an ABI ≥1.4. The mean (standard deviation [SD]) age was 72.1 (7.6) years, and 42.1% of patients were women. Patients with ABI ≥1.4 were older, more frequently male, and diabetic. Multivariable logistic regression analysis showed an association between ABI ≥1.4 and serum levels of PCSK9 >1150 pg/ml (odds ratio [OR], 1.649; 95% confidence interval [CI], 1.047-2.598; P = 0.031). During a median follow-up of 41 months, 113 deaths occurred. In multivariable Cox regression analysis, an ABI ≥1.4 (hazard ratio [HR], 1.626; 95% CI, 1.024-2.582; P = 0.039), CHA 2 DS 2 -VASc score (HR, 1.249; 95% CI, 1.088-1.434; P = 0.002), antiplatelet drug use (HR, 1.775; 95% CI, 1.153-2.733; P = 0.009), and PCSK9 >2060 pg/ml (HR, 2.200; 95% CI, 1.437-3.369; P <0.001) were associated with all-cause death. Conclusions:In AF patients, PCSK9 levels relate to an abnormally high ABI ≥1.4. Our data suggest PCSK9 role in contributing to vascular calcification in AF patients.

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“…Control rats received water or sodium nitrite (daily 15 mg/kg via gavage) [ 12 ] for 1 or 7 days. Omeprazole-treated rats (daily 10 mg/kg; intraperitonially) [ 22 ] received the same doses of sodium nitrite or water. The animals were euthanized at the end of each treatment period (1 or 7 days).…”

Section: Methodsmentioning

confidence: 99%

“…Omeprazole is a commonly prescribed proton pump inhibitor, which, in addition to rising gastric pH, may cause a variety of other deleterious effects including impaired endogenous NO formation [ 20 , 21 ]. While this effect has been initially attributed to inhibited NOS enzyme activity, it is now clear that omeprazole also interferes with gastric nitrite bioactivation to NO and affects the increases in the concentrations of S-nitrosothiols and other nitrosylated species after oral nitrite administration [ 22 , 23 ]. Consequently, the use of omeprazole, which attenuates nitrite-induced increases in NO-related metabolites generated in the stomach [ 21 ], may also affect the increases in tissue storage of NO metabolites after oral nitrite administration.…”

Section: Introductionmentioning

confidence: 99%

The Skeletal Muscle, the Heart, and the Liver Are the Major Organs of the Accumulation of Nitric Oxide Metabolites after Oral Nitrite Treatment

Lima-Silva,

Rebelo,

Barros

et al. 2024

Antioxidants

Self Cite

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Nitrite is a nitric oxide (NO) metabolite, which may be bioactivated to generate NO in vivo and supplement endogenous NO formation, especially in cardiovascular and metabolic diseases. However, it is not known whether treatment with oral nitrite results in the accumulation of NO metabolites in different organs. Moreover, treatment with omeprazole, an inhibitor of gastric acid secretion, severely affects the gastric formation of S-nitrosothiols induced with oral nitrite treatment. However, no previous study has examined whether omeprazole affects the nitrite-induced accumulation of NO metabolites in different organs. This study examined in rats the effects of oral sodium nitrite treatment (15 mg/kg via gavage for 1 or 7 days) associated with omeprazole (10 mg/kg or vehicle) on nitrite and nitrate and nitrosylated species (RXNO) concentrations (measured using ozone-based chemiluminescence methods) assessed in the plasma, aorta, heart, liver, brain, and muscle. While our results showed that NO metabolite accumulation in different organs is not uniform, we found that the skeletal muscle, the heart, and the liver accumulate NO metabolites, particularly RXNO. This response was significantly attenuated by omeprazole in the heart and in the skeletal muscle. Together, these findings may indicate that the skeletal muscle, the heart, and the liver are major reservoir sites for NO metabolites after oral nitrite treatment, with major increases in nitrosylated species.

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Omeprazole induces vascular remodeling by mechanisms involving xanthine oxidoreductase and matrix metalloproteinase activation

Cited by 9 publications

References 54 publications

Allopurinol Blocks Aortic Aneurysm in a Mouse Model of Marfan Syndrome via Reducing Aortic Oxidative Stress

Allopurinol Blocks Aortic Aneurysm in a Mouse Model of Marfan Syndrome via Reducing Aortic Oxidative Stress

Association of proprotein convertase subtilisin/kexin type 9 (PCSK9) levels with abnormally high ankle-brachial index in atrial fibrillation

The Skeletal Muscle, the Heart, and the Liver Are the Major Organs of the Accumulation of Nitric Oxide Metabolites after Oral Nitrite Treatment

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