Journal
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
Volume 149, Issue -, Pages 106-117Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2015.01.015
Keywords
15-HETE; MMP-2; STAT3; Adventitia fibroblast; Migration
Funding
- National Natural Science Foundation of China [81300036]
- China Postdoctoral Science Foundation [2013M541410]
- 7th China Postdoctoral Science Special Foundation [2014T70367]
- state Key Laboratory of Ministry of Education, China [2013015]
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Objective: Vascular adventitial fibroblasts (VAFs) migration was involved in neointima formation, and increased 15-HETE levels contributed to vascular remodeling. However, how 15-HETE-induced VAF migration was not clear. Methods and results: 15-HETE-stimulated VAF phenotypic changes and migration as measured by the wound healing assay required STAT3 phosphorylation. JNK1 and CREB inhibition blocked 15-HETE-induced STAT3 activation and VAF changes. 15-HETE-induced MMP-2 expression and secretion were analyzed by Western blot and ELISA, respectively. MMP-2 knockdown blocked VAF migration and phenotypic alterations. JNK1, STAT3 and CREB blockade suppressed 15-HETE-induced MMP-2 expression in VAFs. MMP-2 promoter activity was assessed by chromatin immunoprecipitation using anti-STAT3 antibodies, which demonstrated that STAT3 was essential for 15-HETE-induced MMP-2 expression. Rats that suffered from hypoxia injury with or without treatment were examined. Pulmonary artery remodeling was obviously observed, and even the media was broken. MMP-2-positive staining was observed in the adventitia and intima. MMP-2 Serum secretion was enhanced as detected by ELISA, and MMP-2 and alpha-SMA protein expressions were increased after inducing hypoxia in the rats, which was restored in rats that had been administrated with NDGA. Conclusion: These results reveal that STAT3-mediated MMP-2 expression is required for 15-HETE induced-VAF migration. (C) 2015 Elsevier Ltd. All rights reserved.
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