title: Pioglitazone reduces angiotensin II-induced COX-2 expression through inhibition of ROS production and ET-1 transcription in vascular cells from spontaneously hypertensive rats.
abstract: Glitazones have anti-inflammatory properties by interfering with the transcription of proinflammatory genes, such as cyclooxygenase (COX)-2, and with ROS production, which are increased in hypertension. This study analyzed whether pioglitazone modulates COX-2 expression in hypertension by interfering with ROS and endothelin (ET)-1. In vivo, pioglitazone (2.5 mg·kg(-1)·day(-1), 28 days) reduced the greater levels of COX-2, pre-pro-ET-1, and NADPH oxidase (NOX) expression and activity as well as O2 (·-) production found in aortas from spontaneously hypertensive rats (SHRs). ANG II increased COX-2 and pre-pro-ET-1 levels more in cultured vascular smooth muscle cells from hypertensive rats compared with normotensive rats. The ETA receptor antagonist BQ-123 reduced ANG II-induced COX-2 expression in SHR cells. ANG II also increased NOX-1 expression, NOX activity, and superoxide production in SHR cells; the selective NOX-1 inhibitor ML-171 and catalase reduced ANG II-induced COX-2 and ET-1 transcription. ANG II also increased c-Jun transcription and phospho-JNK1/2, phospho-c-Jun, and p65 NF-κB subunit nuclear protein expression. SP-600125 and lactacystin, JNK and NF-κB inhibitors, respectively, reduced ANG II-induced ET-1, COX-2, and NOX-1 levels and NOX activity. Pioglitazone reduced the effects of ANG II on NOX activity, NOX-1, pre-pro-ET-1, COX-2, and c-Jun mRNA levels, JNK activation, and nuclear phospho-c-Jun and p65 expression. In conclusion, ROS production and ET-1 are involved in ANG II-induced COX-2 expression in SHRs, explaining the greater COX-2 expression observed in this strain. Furthermore, pioglitazone inhibits ANG II-induced COX-2 expression likely by interfering with NF-κB and activator protein-1 proinflammatory pathways and downregulating ROS production and ET-1 transcription, thus contributing to the anti-inflammatory properties of glitazones.
authors.affiliation: Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Alcorcón, Spain; and.
authors.forename: Jose V
authors.initials: JV
authors.lastname: Pérez-Girón
authors.affiliation: Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Alcorcón, Spain; and.
authors.forename: Roberto
authors.initials: R
authors.lastname: Palacios
authors.affiliation: Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Alcorcón, Spain; and.
authors.forename: Angela
authors.initials: A
authors.lastname: Martín
authors.affiliation: Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Alcorcón, Spain; and.
authors.forename: Raquel
authors.initials: R
authors.lastname: Hernanz
authors.affiliation: Departamento de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Aguado
authors.affiliation: Departamento de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez-Revelles
authors.affiliation: Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Alcorcón, Spain; and.
authors.forename: María T
authors.initials: MT
authors.lastname: Barrús
authors.affiliation: Departamento de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
authors.affiliation: Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, Alcorcón, Spain; and mariajesus.alonso@urjc.es.
authors.forename: María J
authors.initials: MJ
authors.lastname: Alonso
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D000077205:Pioglitazone; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D019332:Endothelin-1; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D000804:Angiotensin II; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D000077205:Pioglitazone
keywords: angiotensin II; cyclooxygenase-2; endothelin-1; hypertension; peroxisome proliferator-activated receptor-γ; reactive oxygen species