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Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension
Entity
UAM. Departamento de Farmacología; Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)Publisher
The British Pharmacological SocietyDate
2015-06-01Citation
10.1111/bph.13117
British Journal of Pharmacology 172.12 (2015): 3159–3176
ISSN
0007-1188 (print); 1476-5381 (on line)DOI
10.1111/bph.13117Funded by
This work was supported by Ministerio de Economía y Competitividad (SAF2012-36400), Instituto de Salud Carlos III (Red de Investigación Cardiovascular RD12/0042/0024 and RD12/0042/0033) and URJC (PRIN13_CS12). AMB was supported by the Ramón y Cajal Program (RYC-2010-06473).Project
Gobierno de España. SAF2012-36400; Gobierno de España. RYC-2010-06473Editor's Version
http://dx.doi.org/10.1111/bph.13117Subjects
TLR4; Hypertension; Oxidative stress; Vascular remodeling; Endothelial dysfunction; FarmaciaNote
This is the peer-reviewed version of the following article: "Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension", British Journal of Pharmacology 172.12 (2015): 3159-76 which has been published in final form at http://dx.doi.org/10.1111/bph.13117 This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-ArchivingRights
© 2015 The British Pharmacological Society.Abstract
Background and Purpose
Toll-like receptor 4 (TLR4) signalling contributes to inflammatory cardiovascular diseases, but its role in hypertension and the associated vascular damage is not known. We investigated whether TLR4 activation contributed to angiotensin II (AngII)-induced hypertension and the associated vascular structural, mechanical and functional alterations.
Experimental Approach
AngII was infused (1.44 mg·kg−1·day−1, s.c.) for 2 weeks in C57BL6 mice, treated with a neutralizing anti-TLR4 antibody or IgG (1 μg·day−1); systolic BP (SBP) and aortic cytokine levels were measured. Structural, mechanical and contractile properties of aortic and mesenteric arterial segments were measured with myography and histology. RT-PCR and Western blotting were used to analyse these tissues and cultured vascular smooth muscle cells (VSMC) from hypertensive rats (SHR).
Key Results
Aortic TLR4 mRNA levels were raised by AngII infusion. Anti-TLR4 antibody treatment of AngII-treated mice normalised: (i) increased SBP and TNF-α, IL-6 and CCL2 levels; (ii) vascular structural and mechanical changes; (iii) altered aortic phenylephrine- and ACh-induced responses; (iv) increased NOX-1 mRNA levels, superoxide anion production and NAD(P)H oxidase activity and effects of catalase, apocynin, ML-171 and Mito-TEMPO on vascular responses; and (v) reduced NO release and effects of L-NAME on phenylephrine-induced contraction. In VSMC, the MyD88 inhibitor ST-2825 reduced AngII-induced NAD(P)H oxidase activity. The TLR4 inhibitor CLI-095 reduced AngII-induced increased phospho-JNK1/2 and p65 NF-κB subunit nuclear protein expression.
Conclusions and Implications
TLR4 up-regulation by AngII contributed to the inflammation, endothelial dysfunction, vascular remodelling and stiffness associated with hypertension by mechanisms involving oxidative stress. MyD88-dependent activation and JNK/NF-κB signalling pathways participated in these alterations
Files in this item
Google Scholar:Hernanz, R.
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Martínez-Revelles, Sonia
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Palacios, R.
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Martín, A.
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Cachofeiro, V.
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Aguado Gómez, Alfredo
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García-Redondo, L.
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Barrús, M. T.
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De Batista, P. R.
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Briones Alonso, Ana María
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Salaices Sánchez, Mercedes
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Alonso, M. J.
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