Ets-1 promotes the progression of cerebral aneurysm by inducing the expression of MCP-1 in vascular smooth muscle cells.
Cerebral aneurysm (CA) rupture is one of the leading causes of stroke death. Recent experimental studies suggest that the pathophysiology of CA is closely associated with inflammation. A transcription factor, Ets-1, has been shown to regulate vascular inflammation and remodeling in a physiological and pathological condition. The expression and role of Ets-1 in CA development has been investigated in this study. Ets-1 was expressed and activated mainly in vascular smooth muscle cells (VSMCs) in both experimentally induced rat CAs and human CA walls by immunohistochemistry, western blotting and enzyme-linked mobility shift assay. The downstream target of Ets-1 in CA development was identified by chromatin immunoprecipitation (CHIP) analysis. CHIP analysis revealed that Ets-1 transactivated monocyte chemoattractant protein-1 (MCP-1) expression in CA walls. Treatment with ets decoy oligodeoxynucleotides resulted in the prevention of CA enlargement, upregulation of MCP-1 expression and increase in macrophage accumulation in CA walls. In conclusion, Ets-1 mediates MCP-1 expression in VSMCs in CA walls, thus promoting the progression of CAs. Inhibition of DNA-binding activity of Ets-1 may lead to the prevention of human CA enlargement and rupture. Results of this study will provide us a clue to a novel therapeutic strategy for CAs.
Aoki
T
T
Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kataoka
H
H
Nishimura
M
M
Ishibashi
R
R
Morishita
R
R
Miyamoto
S
S
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D006801:Humans; D007150:Immunohistochemistry; D002532:Intracranial Aneurysm / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018932:Chemokine CCL2; D050784:Proto-Oncogene Protein c-ets-1