A novel nitroalkene-L-tocopherol analogue inhibits inflammation and ameliorates atherosclerosis in apoE knockout mice

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Título

A novel nitroalkene-L-tocopherol analogue inhibits inflammation and ameliorates atherosclerosis in apoE knockout mice

Tema

ATEROESCLEROSIS
TOCOFEROL
ANTIINFLAMATORIOS
BIBLIOGRAFIA NACIONAL QUIMICA
2019

Abstract

BACKGROUND AND PURPOSE: Atherosclerosis is characterized by chronic low-grade inflammation with concomitant lipid accumulation in the arterial wall. Anti-inflammatory and anti-atherogenic properties have been described for a novel class of endogenous nitroalkenes (nitrated-unsaturated fatty acids), formed during inflammation and digestion/absorption processes. The lipid-associated antioxidant α-tocopherol is transported systemically by LDL particles including to the atheroma lesions. To capitalize on the overlapping and complementary salutary properties of endogenous nitroalkenes and α-tocopherol, we designed and synthesized a novel nitroalkene-α-tocopherol analogue (NATOH) to address chronic inflammation and atherosclerosis, particularly at the lesion sites. EXPERIMENTAL APPROACH: We synthesized NATOH, determined its electrophilicity and antioxidant capacity and studied its effects over pro-inflammatory and cytoprotective pathways in macrophages in vitro. Moreover, we demonstrated its incorporation into lipoproteins and tissue both in vitro and in vivo, and determined its effect on atherosclerosis and inflammatory responses in vivo using the Apo E knockout mice model. KEY RESULTS: NATOH exhibited similar antioxidant capacity to α-tocopherol and, due to the presence of the nitroalkenyl group, like endogenous nitroalkenes, it exerted electrophilic reactivity. NATOH was incorporated in vivo into the VLDL/LDL lipoproteins particles to reach the atheroma lesions. Furthermore, oral administration of NATOH down-regulated NF-κB-dependent expression of pro-inflammatory markers (including IL-1β and adhesion molecules) and ameliorated atherosclerosis in Apo E knockout mice. CONCLUSIONS AND IMPLICATIONS: In toto, the data demonstrate a novel pharmacological strategy for the prevention of atherosclerosis based on a creative, natural and safe drug delivery system of a non-conventional anti-inflammatory compound (NATOH) with significant potential for clinical application.

Autor

Rodríguez Duarte, Jorge.
Galliussi, Germán.
Dapueto, Rosina
Rosello, Jessica
Malacrida, Leonel
Kamaid, Andrés
Schopfer, Francisco J.
Escande, Carlos
Batthyány Dighiero, Carlos Ignacio.

Fuente

British Journal of Pharmacology  v. 176, no. 6, 2019. --p. 757-772

Editor

British Pharmacological Society

Fecha

2019

Derechos

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PDF

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Tipo

Artículo

Identificador

DOI:10.1111/bph.14561

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PDF
Fecha de agregación
December 2, 2019
Colección
Bibliografía Nacional Química
Tipo de Elemento
Document
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Citación
Rodríguez Duarte, Jorge., “A novel nitroalkene-L-tocopherol analogue inhibits inflammation and ameliorates atherosclerosis in apoE knockout mice,” RIQUIM - Repositorio Institucional de la Facultad de Química - UdelaR, accessed December 14, 2019, http://riquim.fq.edu.uy/items/show/5928.
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