Activation of PKC-ε and ERK1/2 participates in shear-induced endothelial MCP-1 expression that is repressed by nitric oxide
✍ Scribed by Chih-Wen Ni; Danny L. Wang; Sheng-Chieh Lien; Jing-Jy Cheng; Yuen-Jen Chao; Hsyue-Jen Hsieh
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- English
- Weight
- 227 KB
- Volume
- 195
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Vascular endothelial cells (ECs) continuously experience hemodynamic shear stress generated from blood flow. Previous studies have demonstrated that shear stress modulates monocyte chemotactic protein‐1 (MCP‐1) expression in ECs. This study explored the roles of protein kinase C (PKC), extracellular signal‐regulated protein kinase (ERK1/2), and nitric oxide (NO) in sheared‐induced MCP‐1 expression in ECs. The activation of PKC‐α and PKC‐ε isoforms was observed in ECs exposed to shear stress. The use of an inhibitor (calphostin C) to PKC‐α and PKC‐ε decreased ERK1/2 activation and MCP‐1 induction by shear, whereas an inhibitor (Go6976) to PKC‐α did not affect ERK1/2 activation or MCP‐1 induction. Inhibition of ERK1/2 activation by PD98059 blocked MCP‐1 induction. Transfection of ECs with an antisense to PKC‐ε abolished the shear inducibility of MCP‐1 promoter. These results demonstrate that PKC‐ε and ERK1/2 participate in shear‐induced MCP‐1 expression. We also examined the regulatory role of NO in MCP‐1 expression. An NO donor (NOC18) suppressed shear‐induced activation of PKC‐ε and ERK1/2, and also repressed MCP‐1 induction. Consistently, overexpression of endothelial nitric oxide synthase (eNOS) to enhance the endogenous generation of NO in ECs decreased the activation of PKC‐ε and ERK1/2, and also inhibited MCP‐1 expression. Taken together, these findings suggest that PKC‐ε and ERK1/2 are critical in the signaling pathway(s) leading to the MCP‐1 expression induced by shear stress. Additionally, this study indicates that NO, by repressing PKC‐ε activity and ERK pathway activation, attenuates shear‐induced MCP‐1 expression. © 2003 Wiley‐Liss, Inc.