Shear Stress Inhibits Homocysteine-Induced Stromal Cell–Derived Factor-1 Expression in Endothelial Cells
| Autor: | Cheng-Nan Chen, Hsin-I Chang, Shu Chien, Ju-Chien Cheng, Mao Lin Sung, Chia Kuang Yen, Heng Jung Chen, Chia Ching Wu |
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| Rok vydání: | 2009 |
| Předmět: |
Male
MAPK/ERK pathway Stromal cell Nitric Oxide Synthase Type III Homocysteine MAP Kinase Kinase 4 Sp1 Transcription Factor Physiology p38 mitogen-activated protein kinases Hyperhomocysteinemia Biology p38 Mitogen-Activated Protein Kinases Article chemistry.chemical_compound Risk Factors Stress Physiological Humans Nitric Oxide Donors Stromal cell-derived factor 1 Phosphorylation RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Cells Cultured Aged Aged 80 and over Sp1 transcription factor Dose-Response Relationship Drug Kinase Endothelial Cells Middle Aged Atherosclerosis Molecular biology Chemokine CXCL12 Cell biology Transcription Factor AP-1 Endothelial stem cell Gene Expression Regulation chemistry biology.protein Female Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation Research. 105:755-763 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.109.206524 |
| Popis: | Rationale : Hyperhomocysteinemia contributes to vascular dysfunction and risks of cardiovascular diseases. Stromal cell–derived factor (SDF)-1, a chemokine expressed by endothelial cells (ECs), is highly expressed in advanced atherosclerotic lesions. The interplays among homocysteine, chemokines, and shear stress in regulating vascular endothelial function are not clearly understood. Objective : To investigate the mechanisms for modulations of EC SDF-1 expression by homocysteine and shear stress. Methods and Results : Homocysteine stimulation induced dose- and time-dependent SDF-1 expression and phosphorylation of mitogen-activated protein kinases extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. By using specific inhibitors, small interfering (si)RNA, and dominant negative mutants, we demonstrated that activation of JNK pathway is critical for the homocysteine-induced SDF-1 expression. Transcription factor ELISA and chromatin immunoprecipitation assays showed that homocysteine increased Sp1- and AP-1–DNA binding activities in ECs. Inhibition of Sp1 and AP-1 activations by specific siRNA blocked the homocysteine-induced SDF-1 promoter activity and expression. Preshearing of ECs for 1 to 4 hours at 20 dyn/cm 2 inhibited the homocysteine-induced JNK phosphorylation, Sp1 and AP-1 activation, and SDF-1 expression. The homocysteine-induced SDF-1 expression was suppressed by NO donor. Inhibitor or siRNA for endothelial NO synthase abolished the shear inhibition of SDF-1 expression. Conclusions : Our findings serve to elucidate the molecular mechanisms underlying the homocysteine induction of SDF-1 expression in ECs and the shear stress protection against this induction. |
| Databáze: | OpenAIRE |
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