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Toll‐like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II ‐induced hypertension
Author(s) -
Hernanz R,
MartínezRevelles S,
Palacios R,
Martín A,
Cachofeiro V,
Aguado A,
GarcíaRedondo L,
Barrús M T,
Batista P R,
Briones A M,
Salaices M,
Alonso M J
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13117
Subject(s) - angiotensin ii , apocynin , vascular smooth muscle , phenylephrine , endocrinology , medicine , nadph oxidase , receptor , chemistry , superoxide , pharmacology , oxidative stress , blood pressure , biochemistry , smooth muscle , enzyme
Background and Purpose Toll‐like receptor 4 ( TLR 4) signalling contributes to inflammatory cardiovascular diseases, but its role in hypertension and the associated vascular damage is not known. We investigated whether TLR 4 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‐ TLR 4 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 TLR 4 mRNA levels were raised by AngII infusion . Anti‐ TLR 4 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 m RNA levels, superoxide anion production and NAD(P)H oxidase activity and effects of catalase, apocynin, ML ‐171 and M ito‐ TEMPO on vascular responses; and (v) reduced NO release and effects of L ‐ NAME on phenylephrine‐induced contraction. In VSMC , the MyD 88 inhibitor ST ‐2825 reduced AngII ‐induced NAD(P)H oxidase activity. The TLR 4 inhibitor CLI ‐095 reduced AngII ‐induced increased phospho‐ JNK 1/2 and p65 NF ‐ κB subunit nuclear protein expression. Conclusions and Implications TLR 4 up‐regulation by AngII contributed to the inflammation, endothelial dysfunction, vascular remodelling and stiffness associated with hypertension by mechanisms involving oxidative stress. MyD 88‐dependent activation and JNK/NF ‐ κB signalling pathways participated in these alterations.