Transient interaction of activated platelets with endothelial cells induces expression of monocyte-chemoattractant protein-1 via a p38 mitogen-activated protein kinase mediated pathway. Implications for atherogenesis.
OBJECTIVE
Activated platelets induce alterations of chemotactic and adhesive properties of endothelial cells, a critical initial step in atherogenesis. We investigated the effect of transient interaction of activated platelets with cultured human umbilical vein endothelial cells (HUVECs) on secretion of monocyte chemoattractant protein-1 (MCP-1), a key molecule in monocyte chemotaxis and transmigration.


RESULTS
Transient interaction of alpha-thrombin-activated platelets with endothelial cells for 10-120 min substantially induced endothelial secretion of MCP-1, monocyte chemotaxis and adhesion to HUVECs. Platelet-induced secretion of MCP-1 and monocyte-endothelium adhesion was reduced by the MAP kinase p38-specific inhibitor SB203580, but not by other kinase inhibitors including PD98059, wortmannin, or rapamycin. In addition, activated platelets induced transcription of a luciferase reporter construct containing a MCP-1 promotor, an effect that could be inhibited by SB203580. Overexpression of dominant-negative mutants of MAP kinase p38, CSBP2-(D168A) and CSBP2-(T180E,Y182E) reduced platelet-induced expression of MCP-1.


CONCLUSIONS
Activation of the p38 MAP kinase and consecutive endothelial secretion of MCP-1 induced through transient interaction of activated platelets might play an important role in atherogenesis.
Dickfeld
T
T
Medical Department, Duke University, Durham, NC, USA.
Lengyel
E
E
May
A E
AE
Massberg
S
S
Brand
K
K
Page
S
S
Thielen
C
C
Langenbrink
K
K
Gawaz
M
M
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001161:Arteriosclerosis / Q000209:etiology*; D001792:Blood Platelets / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D018929:Cell Culture Techniques; D018932:Chemokine CCL2 / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009000:Monocytes / Q000502:physiology; D015539:Platelet Activation / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D014178:Translocation, Genetic; D014471:Umbilical Veins / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases
D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580