The Melatonin Derivative ITH13001 Prevents Hypertension and Cardiovascular Alterations in Angiontensin II-Infused Mice
dc.contributor.author | Martínez-Casales, Marta | |
dc.contributor.author | Hernanz, Raquel | |
dc.contributor.author | González-Carnicero, Zoe | |
dc.contributor.author | Barrús, María Teresa | |
dc.contributor.author | Martín, Ángela | |
dc.contributor.author | Briones, Ana M. | |
dc.contributor.author | Michalska, Patrycja | |
dc.contributor.author | León, Rafael | |
dc.contributor.author | Pinilla, Estefano | |
dc.contributor.author | Simonsen, Ulf | |
dc.contributor.author | Alonso, María Jesús | |
dc.date.accessioned | 2024-06-28T06:50:47Z | |
dc.date.available | 2024-06-28T06:50:47Z | |
dc.date.issued | 2024-01-18 | |
dc.description.abstract | Inflammatory mechanisms and oxidative stress seem to contribute to the pathogenesis of hypertension. ITH13001 is a melatonin-phenyl-acrylate hybrid that moderately induces the antioxidant transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) and has a potent oxidant scavenging effect compared with other derivatives of its family. Here we investigated the effect of ITH13001 on hypertension and the associated cardiovascular alterations. Angiotensin II (AngII)-infused mice were treated with ITH13001 (1 mg/kg per day, i.p.) for 2 weeks. The ITH13001 treatment prevented: 1) the development of hypertension, cardiac hypertrophy, and increased collagen and B-type natriuretic peptide (Bnp) expression in the heart; 2) the reduction of elasticity, incremental distensibility, fenestrae area, intraluminal diameter, and endothelial cell number in mesenteric resistance arteries (MRA); 3) the endothelial dysfunction in aorta and MRA; 4) the plasma and cardiovascular oxidative stress and the reduced aortic nitric oxide (NO) bioavailability; 5) the increased cardiac levels of the cytokines interleukin (IL)-1β, IL-6, and C-C motif chemokine ligand 2 (Ccl2), the T cell marker cluster of differentiation 3 (Cd3), the inflammasome NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), the proinflammatory enzymes inducible nitric oxide synthase (iNOS) and COX-2, the toll-like receptor 4 (TLR4) adapter protein myeloid differentiation primary response 88 (MyD88), and the nuclear factor kappa B (NF-κB) subunit p65; 6) the greater aortic expression of the cytokines tumor necrosis factor alpha (Tnf-α), Ccl2 and IL-6, Cd3, iNOS, MyD88, and NLRP3. Although ITH13001 increased nuclear Nrf2 levels and heme oxygenase 1 (HO-1) expression in vascular smooth muscle cells, both cardiac and vascular Nrf2, Ho-1, and NADPH quinone dehydrogenase 1 (Nqo1) levels remained unmodified irrespective of AngII infusion. Summarizing, ITH13001 improved hypertension-associated cardiovascular alterations independently of Nrf2 pathway activation, likely due to its direct antioxidant and anti-inflammatory properties. Therefore, ITH13001 could be a useful therapeutic strategy in patients with resistant hypertension. SIGNIFICANCE STATEMENT: Despite the existing therapeutic arsenal, only half of the patients treated for hypertension have adequately controlled blood pressure; therefore, the search for new compounds to control this pathology and the associated damage to end-target organs (cerebral, cardiac, vascular, renal) is of particular interest. The present study demonstrates that a new melatonin derivative, ITH13001, prevents hypertension development and the associated cardiovascular alterations due to its antioxidant and anti-inflammatory properties, making this compound a potential candidate for treatment of resistant hypertensive patients. | es |
dc.identifier.citation | Martínez-Casales M, Hernanz R, González-Carnicero Z, Barrús MT, Martín A, Briones AM, Michalska P, León R, Pinilla E, Simonsen U, Alonso MJ. The Melatonin Derivative ITH13001 Prevents Hypertension and Cardiovascular Alterations in Angiotensin II-Infused Mice. J Pharmacol Exp Ther. 2024 Jan 17;388(2):670-687. doi: 10.1124/jpet.123.001586. PMID: 38129126. | es |
dc.identifier.doi | 10.1124/jpet.123.001586 | es |
dc.identifier.issn | 0022-3565 (online) | |
dc.identifier.issn | 1521-0103 (print) | |
dc.identifier.uri | https://hdl.handle.net/10115/35598 | |
dc.language.iso | eng | es |
dc.publisher | American Society for Pharmacology and Experimental Therapeutics | es |
dc.rights | Atribución-CompartirIgual 4.0 Internacional | * |
dc.rights.accessRights | info:eu-repo/semantics/closedAccess | es |
dc.rights.uri | http://creativecommons.org/licenses/by-sa/4.0/ | * |
dc.subject | endothelium | es |
dc.subject | hypertension | es |
dc.subject | oxidative stress/antioxidants | es |
dc.subject | inflammation | es |
dc.subject | Nrf2 | es |
dc.title | The Melatonin Derivative ITH13001 Prevents Hypertension and Cardiovascular Alterations in Angiontensin II-Infused Mice | es |
dc.type | info:eu-repo/semantics/article | es |
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