MDM2: a novel mineralocorticoid-responsive gene involved in aldosterone-induced human vascular structural remodeling.
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.
Nakamura
Yasuhiro
Y
Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Suzuki
Saya
S
Suzuki
Takashi
T
Ono
Katsuhiko
K
Miura
Ikumi
I
Satoh
Fumitoshi
F
Moriya
Takuya
T
Saito
Haruo
H
Yamada
Shogo
S
Ito
Sadayoshi
S
Sasano
Hironobu
H
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
D008901:Mineralocorticoids; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D051736:Proto-Oncogene Proteins c-mdm2