title: Activation of AP-1 through reactive oxygen species by angiotensin II in rat cardiomyocytes.
abstract: Cardiovascular pathogenesis induced by angiotensin II (Ang-II) is a complex process often connected to oxidative stress. In the present study we show that, 4 h after addition, Ang-II induces a four- to fivefold increase in AP-1 activity in cultured neonatal rat cardiomyocytes and that the intracellular level of reactive oxygen species (ROS) correlates with the extent of AP-1 binding activity. Ang-II stimulated ROS generation in rat cardiomyocytes in a dose- and time-dependent manner. These effects of Ang-II were suppressed by the Ang-II receptor type I (AT1) inhibitor CV-11974 as well as by the antioxidants diphenylene iodonium (DPI) and N-acetyl-L-cysteine (NAC), but not by AT2 antagonist PD 122319. Furthermore, Ang-II induced a two- to threefold increase in protein synthesis and cell size during 12-24 h, which could be inhibited by CV-11974 as well as by DPI and NAC. Because the rat cardiomyocytes strongly expressed gp91(phox), this suggests that ROS generated in a gp91-containing NADPH oxidase are involved in signal transduction leading to AP-1 activation. Together, these findings indicate that Ang-II elicits the activation of the redox-sensitive AP-1 via ROS through AT1, resulting in effects on cardiomyocyte function such as hypertrophy.
authors.affiliation: Institute of Laboratory Medicine and Pathobiochemistry, Charité Medical Center, Humboldt University Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. shuling.wu@charite.de
authors.forename: Shuling
authors.initials: S
authors.lastname: Wu
authors.forename: Jianping
authors.initials: J
authors.lastname: Gao
authors.forename: Carsten
authors.initials: C
authors.lastname: Ohlemeyer
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
authors.forename: Hans
authors.initials: H
authors.lastname: Niessen
authors.forename: Eckart
authors.initials: E
authors.lastname: Köttgen
authors.forename: Reinhard
authors.initials: R
authors.lastname: Gessner
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D018808:Transcription Factor AP-1; D000804:Angiotensin II; C007517:diphenyleneiodonium; D019255:NADPH Oxidases; C081643:candesartan; D000111:Acetylcysteine