Inducible cAMP early repressor inhibits growth of vascular smooth muscle cell.
OBJECTIVE
The role of inducible cAMP early repressor (ICER), a transcriptional repressor, in the vascular remodeling process has not been determined. We examined whether ICER affects growth of vascular smooth muscle cells (VSMCs).


RESULTS
Semi-quantitative RT-PCR and Western blot analysis showed that expression of ICER was increased in beraprost (a prostaglandin I2 analogue)-stimulated VSMCs in a time- and dose-dependent manner. The induction of ICER was inhibited by pretreatment with H89, a protein kinase A (PKA) inhibitor, suggesting that PKA mediates the induction of ICER expression. Beraprost suppressed platelet-derived growth factor-induced thymidine incorporation in VSMCs, which was reversed by transfection of short interfering RNA for ICER, not by scramble RNA. Overexpression of ICER by an adenovirus vector attenuated neointimal formation (intima/media ratio) by 50% compared with overexpression of LacZ. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells was increased and the number of Ki-67-positive cells was decreased in ICER-transduced artery.


CONCLUSIONS
These results suggest that ICER induces apoptosis and inhibits proliferation of VSMCs, and plays a critical role in beraprost-mediated suppression of VSMC proliferation. ICER may be an important endogenous inhibitor of vascular proliferation.
Ohtsubo
Hideki
H
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashiku, 812-8582 Fukuoka, Japan.
Ichiki
Toshihiro
T
Miyazaki
Ryohei
R
Inanaga
Keita
K
Imayama
Ikuyo
I
Hashiguchi
Yasuko
Y
Sadoshima
Junichi
J
Sunagawa
Kenji
K
D000704:Analysis of Variance; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D051786:Cyclic AMP Response Element Modulator / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000254:growth & development*; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
D012333:RNA, Messenger; D051786:Cyclic AMP Response Element Modulator; C048081:beraprost; D011464:Epoprostenol