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CELLULAR MOLECULAR BIOLOGY LETTERShttp://www.cmbl.org.plReceived: 17 July 2010 Final form accepted: 03 February 2011 Published online: 16 February 2011 Volume 16 (2011) pp 226-235 DOI: 10.2478/s11658-011-0002-3 ?2011 by the University of Wroclaw, PolandResearch article THE MITOCHONDRIA MEDIATE THE INDUCTION OF NOX1 GENE EXPRESSION BY ALDOSTERONE IN AN ATF-1-DEPENDENT MANNER YANPING FU1,?, GANG SHI2,? YONG WU3, YASUYUKI KAWAI4, QING TIAN1, LINLIN YUE1, QINJIE XIA1, ISAMU MIYAMORI4 and CHUNYUAN FAN1,5* 1 Department of Nephrology, West China Hospital of Sichuan University, Guoxue Lane 37, WuHou Zone, Chengdu, 610041, China, 2State Key Laboratory of Biotherapy, SiChuan University, PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/12027669 1 Keyuan Road 4, GaoPeng Street, High Technological Development Zone, Chengdu, 610041, China, 3The Second OutPatient Institutions of the PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/17184506 Chengdu Military Region, Chengdu 610041, China, 4 Third Department of Internal Medicine, Faculty of Medical 5-(2-Fluorophenyl)-1H-pyrrole-3-carbonitrile Sciences, University of Fukui, Fukui, Japan, 5The Second People's Hospital in Chengdu, Chengdu 610041, China Abstract: High aldosterone (Ald) levels can induce hypertrophy of vascular smooth muscle cells (VSMCs), which carries high risks of heart failure. A previous study showed that Ald induces hypertrophy of VSMCs by upregulating NOX1, a catalytic subunit of NADPH oxidase that produces superoxides. However, the precise mechanism remains unknown. Diphenylene iodonium (DPI) is known as an inhibitor of complex I in the mitochondrial respiratory chain, and it was also found to almost completely suppress the induction of NOX1 mRNA and the phosphorylation of activating transcription factor (ATF-1) by PGF2 or PDGF in a rat VSMC cell line. In this study, we found that the Ald-induced phosphorylation of ATF-1 and NOX1 expression was significantly suppressed by DPI. Silencing of ATF-1 gene expression attenuated the induction of NOX1 mRNA expression, and over-expression of ATF-?These authors contributed equally (R)-1-(3-Chlorophenyl)ethan-1-ol to this work* Author for correspondence. e-mail: fanchunyuan2009@yahoo.cn, phone: +86-2881812896, fax: +86-28-85164005 Abbreviations used: ALD ?aldosterone; ATF ?activating transcription factor-1; CRE ?cAMP-response element; CREB ?CRE-binding protein; DMEM ?Dulbecco's modified Eagle's medium; DPI ?diphenylene iodonium; FBS ?fetal bovine serum; MnTBAP ?Mn(III)tetrakis(4-benzoic 6-Trichloronicotinic acid 8-Oxa-3-azabicyclo[3.2.1]octane hydrochloride 3-Hydroxyanthranilic acid PigmentRed179 4-CHLORO-2-NITROBENZALDEHYDE Diethyl 4-oxocyclohexane-1)porphyrin chloride; MR ?mineralocorticoid receptor; MTT,3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; NOX1 ?NADPH oxidase 1; ROS ?reactive oxygen species; VSMC ?vascular smooth muscle cellCELLULAR MOLECULAR BIOLOGY LETTERSrestored Ald-induced NOX1 expression. On the basis of this data, we show that the mitochondria mediate aldosterone-induced NOX1 gene expression in an ATF-1-dependent manner. Key words: Aldosterone, Mitochondria, ATF-1, NOX1, VSMC INTRODUCTION Recently, more and more studies have demonstrated that Ald has direct effects on the cardiovascular system independent of renal salt and water regulation [1-3]. Ald induces cardiac fibrosis independently of other renin-angiotensin system components. Accumulation and hypertrophy of VSMCs are characteristic for atherosclerotic, restenotic and hypertensive vascular diseases [4]. Many factors are involved in the mediation of VSMC growth. Among them, ROS play a vital role. A variety of cellular enzymes are potential sources of ROS, including microsomal cytoc.