title: MDM2: a novel mineralocorticoid-responsive gene involved in aldosterone-induced human vascular structural remodeling.
abstract: Aldosterone has been demonstrated to play an important role in the pathogenesis of various cardiovascular diseases. Vascular structural remodeling, including vascular smooth muscle cell (VSMC) proliferation, has been also reported in small resistance arteries of patients with primary aldosteronism. Therefore, in this study, we examined whether genes involved in the regulation of the cell cycle were induced by aldosterone alone in cultured human VSMCs and in human small resistance arteries. Results of these studies eventually demonstrated that MDM2, one of the genes involved in anti-apoptosis and cell growth, was markedly increased in mineralocorticoid receptor (MR)-positive VSMCs by aldosterone in all microarray, reverse transcriptase-polymerase chain reaction, immunoblotting, and immunofluorescence analyses. In addition, an analysis using small interfering RNA demonstrated that this gene product was involved in cell proliferation of VSMCs induced by aldosterone. Eplerenone, a specific MR antagonist, inhibited this gene induction by aldosterone in VSMCs. MDM2 protein was also more abundant in VSMCs of small resistance arteries in patients with primary aldosteronism compared with a control population. MDM2 is therefore considered one of the mineralocorticoid-responsive genes that regulates cell proliferation of VSMCs induced by MR-mediated aldosterone stimulation, possibly playing an important role in aldosterone-induced vascular structural remodeling.
authors.affiliation: Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Saya
authors.initials: S
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Ono
authors.forename: Ikumi
authors.initials: I
authors.lastname: Miura
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Satoh
authors.forename: Takuya
authors.initials: T
authors.lastname: Moriya
authors.forename: Haruo
authors.initials: H
authors.lastname: Saito
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamada
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D046228:Microarray Analysis; D008901:Mineralocorticoids / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D008901:Mineralocorticoids; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D051736:Proto-Oncogene Proteins c-mdm2