title: Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia.
abstract: Emerging data point the crosstalk between dyslipidemia and renin-angiotensin system (RAS). Advanced dyslipidemia is described to induce RAS activation in the vasculature. However, the interplay between early dyslipidemia and the RAS remains unexplored. Knowing that hamsters and humans have a similar lipid profile, we investigated the effects of early and advanced dyslipidemia on angiotensin II-induced contraction. Cumulative concentration-response curves for angiotensin II (1.0pmol/l to 1.0µmol/l) were obtained in the hamster thoracic aorta. We also investigated the modulatory action of NAD(P)H oxidase on angiotensin II-induced contraction using ML171 (Nox-1 inhibitor, 0.5µmol/l) and VAS2870 (Nox-4 inhibitor, 5µmol/l). Early dyslipidemia was detected in hamsters treated with a cholesterol-rich diet for 15 days. Early dyslipidemia decreased the contraction induced by angiotensin II and the concentration of Nox-4-derived hydrogen peroxide. Advanced dyslipidemia, observed in hamsters treated with cholesterol-rich diet for 30 days, restored the contractile response induced by angiotensin II by compensatory mechanism that involves Nox-4-mediated oxidative stress. The hyporresponsiveness to angiotensin II may be an auto-inhibitory regulation of the angiotensinergic function during early dyslipidemia in an attempt to reduce the effects of the upregulation of the vascular RAS during the advanced stages of atherogenesis. The recovery of vascular angiotensin II functionality during the advanced phases of dyslipidemia is the result of the upregulation of redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the recovery of vascular function. Taken together, our findings show the early phase of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions.
authors.affiliation: Laboratory of Pharmacology, Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Electronic address: pri_fcbio@yahoo.com.br.
authors.forename: Priscila Cristina
authors.initials: PC
authors.lastname: Pereira
authors.affiliation: Laboratory of Vascular Injury, Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Larissa
authors.initials: L
authors.lastname: Pernomian
authors.affiliation: Laboratory of Pharmacology, Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Hariane
authors.initials: H
authors.lastname: Côco
authors.affiliation: Laboratory of Vascular Injury, Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Mayara Santos
authors.initials: MS
authors.lastname: Gomes
authors.affiliation: Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: João José
authors.initials: JJ
authors.lastname: Franco
authors.affiliation: Laboratory of Pharmacology, Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Kátia Colombo
authors.initials: KC
authors.lastname: Marchi
authors.affiliation: Laboratory of Pharmacology, School of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Ulisses Vilela
authors.initials: UV
authors.lastname: Hipólito
authors.affiliation: Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Sergio Akira
authors.initials: SA
authors.lastname: Uyemura
authors.affiliation: Laboratory of Pharmacology, School of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Carlos Renato
authors.initials: CR
authors.lastname: Tirapelli
authors.affiliation: Laboratory of Vascular Injury, Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: de Oliveira
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D002374:Catalase / Q000378:metabolism; D006224:Cricetinae; D059305:Diet, High-Fat / Q000009:adverse effects; D050171:Dyslipidemias / Q000378:metabolism* / Q000503:physiopathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D017382:Reactive Oxygen Species; D000804:Angiotensin II; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D019255:NADPH Oxidases
keywords: Angiotensin AT(1) receptors; Dyslipidemia; Golden Syrian hamsters; Hydrogen peroxide; NAD(P)H oxidase