1. The Melatonin Derivative ITH13001 Prevents Hypertension and Cardiovascular Alterations in Angiotensin II-Infused Mice.
- Author
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Martínez-Casales M, Hernanz R, González-Carnicero Z, Barrús MT, Martín A, Briones AM, Michalska P, León R, Pinilla E, Simonsen U, and Alonso MJ
- Subjects
- Humans, Mice, Animals, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Angiotensin II, Antioxidants pharmacology, Antioxidants therapeutic use, Antioxidants metabolism, Interleukin-6 metabolism, NF-E2-Related Factor 2 metabolism, Myeloid Differentiation Factor 88 metabolism, NF-kappa B metabolism, Cytokines metabolism, Anti-Inflammatory Agents pharmacology, Melatonin pharmacology, Melatonin therapeutic use, Hypertension chemically induced, Hypertension drug therapy, Hypertension prevention & control
- 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- κ B) 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., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2024
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