© 1995 American Heart Association, Inc.
Articles |
Mechanical Strain Induces Monocyte Chemotactic Protein-1 Gene Expression in Endothelial Cells
Effects of Mechanical Strain on Monocyte Adhesion to Endothelial Cells
From the Cardiovascular Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC.
Abstract Monocyte chemotactic protein-1 (MCP-1), a potent monocyte chemoattractant secreted by endothelial cells (ECs), is believed to play a key role in the early events of atherogenesis. Since vascular ECs are constantly subjected to mechanical stresses, we examined how cyclic strain affects the expression of the MCP-1 gene in human ECs grown on a flexible membrane base deformed by sinusoidal negative pressure (peak level, -16 kPa at 60 cycles per minute). Northern blot analysis demonstrated that the MCP-1 mRNA levels in ECs subjected to strain for 1, 5, or 24 hours were double those in control ECs (P<.05). This strain-induced increase was mainly serum independent, and MCP-1 mRNA level returned to its control basal level 3 hours after release of strain. Culture media from strained ECs contained approximately twice the MCP-1 concentration and more than twice the monocyte chemotactic activity of media from control ECs (P<.05). Pretreatment of collected media with anti–MCP-1 antibody suppressed such activity. Monocyte adhesion to ECs subjected to strain for 12 hours was 1.8-fold greater than adhesion to unstrained control ECs (P<.05). A protein kinase C inhibitor, calphostin C, abolished the strain-induced MCP-1 gene expression. In addition, cAMP- or cGMP-dependent protein kinase inhibitors (KT5720 and KT5823, respectively) partially inhibited such expression. Pretreatment with EGTA or the intracellular Ca2+ chelator BAPTA/AM strongly suppressed the strain-induced MCP-1 mRNA. Verapamil, a Ca2+ channel blocker, greatly reduced MCP-1 mRNA levels in both strained and unstrained ECs. These results indicate that mechanical strain can stimulate monocyte chemotaxis and adhesion by increasing MCP-1 gene expression in ECs. This increased gene expression is predominantly mediated via the protein kinase C pathway and requires Ca2+ influx. Such strain-induced MCP-1 expression might contribute to the trapping of monocytes in the subendothelial space. Strain-induced gene expression might provide a molecular mechanism for the role of hypertension in atherogenesis.
Key Words: atherosclerosis • endothelial cells • gene regulation • mechanical strain • monocyte chemotactic protein-1
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