title: Toll-like receptor 4 upregulation by angiotensin II contributes to hypertension and vascular dysfunction through reactive oxygen species production.
abstract: Hypertension is considered as a low-grade inflammatory disease, with adaptive immunity being an important mediator of this pathology. TLR4 may have a role in the development of several cardiovascular diseases; however, little is known about its participation in hypertension. We aimed to investigate whether TLR4 activation due to increased activity of the renin-angiotensin system (RAS) contributes to hypertension and its associated endothelial dysfunction. For this, we used aortic segments from Wistar rats treated with a non-specific IgG (1 µg/day) and SHRs treated with losartan (15 mg/kg·day), the non-specific IgG or the neutralizing antibody anti-TLR4 (1 µg/day), as well as cultured vascular smooth muscle cells (VSMC) from Wistar and SHRs. TLR4 mRNA levels were greater in the VSMC and aortas from SHRs compared with Wistar rats; losartan treatment reduced those levels in the SHRs. Treatment of the SHRs with the anti-TLR4 antibody: 1) reduced the increased blood pressure, heart rate and phenylephrine-induced contraction while it improved the impaired acetylcholine-induced relaxation; 2) increased the potentiation of phenylephrine contraction after endothelium removal; and 3) abolished the inhibitory effects of tiron, apocynin and catalase on the phenylephrine-induced response as well as its enhancing effect of acetylcholine-induced relaxation. In SHR VSMCs, angiotensin II increased TLR4 mRNA levels, and losartan reduced that increase. CLI-095, a TLR4 inhibitor, mitigated the increases in NAD(P)H oxidase activity, superoxide anion production, migration and proliferation that were induced by angiotensin II. In conclusion, TLR4 pathway activation due to increased RAS activity is involved in hypertension, and by inducing oxidative stress, this pathway contributes to the endothelial dysfunction associated with this pathology. These results suggest that TLR4 and innate immunity may play a role in hypertension and its associated end-organ damage.
authors.affiliation: Dept. of Biochemistry, Physiology and Molecular Genetics, Universidad Rey Juan Carlos, Alcorcón, Spain; Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil.
authors.forename: Priscila R
authors.initials: PR
authors.lastname: De Batista
authors.affiliation: Dept. of Biochemistry, Physiology and Molecular Genetics, Universidad Rey Juan Carlos, Alcorcón, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Palacios
authors.affiliation: Dept. of Biochemistry, Physiology and Molecular Genetics, Universidad Rey Juan Carlos, Alcorcón, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Martín
authors.affiliation: Dept. of Biochemistry, Physiology and Molecular Genetics, Universidad Rey Juan Carlos, Alcorcón, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Hernanz
authors.affiliation: Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil.
authors.forename: Cindy T
authors.initials: CT
authors.lastname: Médici
authors.affiliation: Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil.
authors.forename: Marito A S C
authors.initials: MA
authors.lastname: Silva
authors.affiliation: Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil.
authors.forename: Emilly M
authors.initials: EM
authors.lastname: Rossi
authors.affiliation: Dept. of Pharmacology, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Aguado
authors.affiliation: Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil.
authors.forename: Dalton V
authors.initials: DV
authors.lastname: Vassallo
authors.affiliation: Dept. of Pharmacology, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
authors.affiliation: Dept. of Biochemistry, Physiology and Molecular Genetics, Universidad Rey Juan Carlos, Alcorcón, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Alonso
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D013481:Superoxides; D000804:Angiotensin II; D010656:Phenylephrine; D019255:NADPH Oxidases; D000109:Acetylcholine
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