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-inflamma-tory properties by interfering with the transcription of proinflamma-tory genes, such as cyclooxygenase (COX)-2, and with ROS produc-tion, which are increased in hypertension. This study analyzedwhether pioglitazone modulates COX-2 expression in hypertension byinterfering with ROS and endothelin (ET)-1. In vivo, pioglitazone (2.5mg·kg 1 ·day 1 , 28 days) reduced the greater levels of COX-2,pre-pro-ET-1, and NADPH oxidase (NOX) expression and activity aswell as O2· production found in aortas from spontaneously hyper-tensive rats (SHRs). ANG II increased COX-2 and pre-pro-ET-1levels more in cultured vascular smooth muscle cells from hyperten-sive rats compared with normotensive rats. The ETA receptor antag-onist BQ-123 reduced ANG II-induced COX-2 expression in SHRcells. ANG II also increased NOX-1 expression, NOX activity, andsuperoxide production in SHR cells; the selective NOX-1 inhibitorML-171 and catalase reduced ANG II-induced COX-2 and ET-1transcription. ANG II also increased c-Jun transcription and phospho-JNK1/2, phospho-c-Jun, and p65 NF- B subunit nuclear proteinexpression. SP-600125 and lactacystin, JNK and NF- B inhibitors,respectively, reduced ANG II-induced ET-1, COX-2, and NOX-1levels and NOX activity. Pioglitazone reduced the effects of ANG IIon NOX activity, NOX-1, pre-pro-ET-1, COX-2, and c-Jun mRNAlevels, JNK activation, and nuclear phospho-c-Jun and p65 expres-sion. In conclusion, ROS production and ET-1 are involved in ANGII-induced COX-2 expression in SHRs, explaining the greater COX-2expression observed in this strain. Furthermore, pioglitazone inhibitsANG II-induced COX-2 expression likely by interfering with NF- Band activator protein-1 proinflammatory pathways and downregulat-ing ROS production and ET-1 transcription, thus contributing to theanti-inflammatory properties of glitazones.