Cellular repressor of E1A-stimulated genes inhibits human vascular smooth muscle cell apoptosis via blocking P38/JNK MAP kinase activation.
Vascular smooth muscle cell (VSMC) apoptosis accelerates atherosclerosis and promotes restenosis following vascular injury. The current study examined the effects of cellular repressor of E1A-stimulated genes (CREG), a novel glycoprotein inhibiting transcription activation, on the regulation of VSMC apoptosis. Serum starvation or treatment of human VSMCs with apoptosis inducers (STS or VP-16) significantly reduced CREG expression and caused caspase-3 activation. CREG downregulation and caspase-3 activation were inversely related, suggesting that reduced CREG expression may contribute to VSMC apoptosis. Both loss-of-function (CREG-DW produced by retroviruses expressing CREG shRNAs) and gain-of-function (CREG-UP produced by retroviral infection with vector pLNCX-CREG) studies were performed to confirm this hypothesis. CREG-DW significantly increased VSMC apoptosis, whereas CREG-UP significantly reduced apoptosis. Moreover, p38 and JNK mitogen-activated protein kinases were significantly upregulated in CREG-DW and significantly reduced in CREG-UP VSMCs. More importantly, CREG-DW-induced VSMC apoptosis was blocked by the p38-specific inhibitor SB203580 or by overexpression of a dominant-negative P38 alpha (p38 alpha AGF). Balloon injury-induced vascular caspase-3 activation was significantly inhibited by treatment with recombinant CREG protein. These results demonstrated for the first time that CREG plays a key role in modulating VSMC apoptosis through the p38 and JNK signal transduction pathways, both in vitro and in situ.
Han
Yaling
Y
Cardiovascular Research Institute and Department of Cardiology, Shenyang Northern Hospital, Shenyang, China. hanyaling@263.net
Wu
Guangzhe
G
Deng
Jie
J
Tao
Jie
J
Guo
Liang
L
Tian
Xiaoxiang
X
Kang
Jian
J
Zhang
Xiaolin
X
Yan
Chenghui
C
D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013895:Thoracic Arteries / Q000473:pathology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017500:Adenovirus E1A Proteins; C114068:CREG1 protein, human; D012097:Repressor Proteins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3