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(Circulation Research. 2009;105:755.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Shear Stress Inhibits Homocysteine-Induced Stromal Cell–Derived Factor-1 Expression in Endothelial Cells

Mao-Lin Sung, Chia-Ching Wu, Hsin-I Chang, Chia-Kuang Yen, Heng Jung Chen, Ju-Chien Cheng, Shu Chien, Cheng-Nan Chen

From the Department of Cardiology (M.-L.S., C.-K.Y.), St Martin De Porres Hospital, Chiayi, Taiwan; Department of Medical Laboratory Science and Biotechnology (M.-L.S., J.-C.C.), China Medical University, Taichung, Taiwan; Department of Cell Biology and Anatomy (C.-C.W.), School of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemical Science and Technology (H.-I.C., C.-N.C.), National Chiayi University, Taiwan; Nursing Department (H.J.C.), Chung Jen College of Nursing, Health Science and Management, Chiayi, Taiwan; and Departments of Bioengineering and Medicine and Institute of Engineering in Medicine (S.C.), University of California at San Diego, La Jolla.

Correspondence to Cheng-Nan Chen, PhD, Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan. E-mail cnchen{at}mail.ncyu.edu.tw

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/cm² 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.

Key Words: homocysteine • endothelial cells • stromal cell–derived factor-1 • shear stress • transcriptional regulation