Endothelin-1 induced proinflammatory markers in the myocardium and leukocytes of guinea-pigs: role of glycoprotein IIB/IIIA receptors.
OBJECTIVE
To assess whether endothelin-1 (ET-1) induces the in vivo expression of inflammatory-related proteins, namely cyclooxygenase-2 (COX-2) and tissue factor, in the myocardium and circulating leukocytes of guinea-pigs. The involvement of platelets was also analyzed.


METHODS
ET-1 (0.013 microg/min) was infused to male guinea-pigs for 45 min in the presence and absence of tirofiban, a nonpeptidic blocker of the glycoprotein IIb/IIIa receptor (GPIIb/IIIa). Tissue factor and COX-2 expression were determined by Western blot.


RESULTS
No changes in mean arterial pressure and heart rate were detected. ET-1-infused guinea-pigs showed a marked increase in the number of platelets expressing activated GPIIb/IIIa receptors (0.8+/-0.03% vs. 6.5+/-0.2%; P<0.05). Tirofiban (10 microg/Kg bw/min) blunted ex vivo platelet aggregation in response to ADP, although only partially reduced COX-2 and tissue factor expression in both the myocardium and leukocytes of ET-1-infused guinea-pigs. The myocardium of platelet-depleted guinea-pigs also showed a reduced COX-2 expression after ET-1 infusion (57+/-3% reduction; P<0.05). In vitro studies demonstrated that platelets (10(7) and 10(9) platelets/well) enhanced ET-1 (10(-7) mol/l)-induced COX-2 expression in heart slices.


CONCLUSIONS
ET-1 stimulated in vivo the expression of the pro-inflammatory proteins COX-2 and tissue factor in the myocardium and in leukocytes by a mechanism GPIIb/IIIa platelet receptors.
Molero
Laura
L
Cardiovascular Research Laboratory, Fundación Jiménez Díaz, Av. Reyes Católicos, 2, Madrid, 28040 Spain.
Farré
Jeronimo
J
García-Mendez
Antonio
A
Jiménez Mateos-Caceres
Petra
P
Carrasco Martín
Carolina
C
Millás
Inmaculada
I
Navarro
Felipe
F
Córdoba
Manuel
M
Casado
Santos
S
López-Farré
Antonio
A
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D019332:Endothelin-1 / Q000494:pharmacology*; D006168:Guinea Pigs; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000378:metabolism; D013268:Stimulation, Chemical; D013925:Thromboplastin / Q000032:analysis / Q000378:metabolism; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D019332:Endothelin-1; D007527:Isoenzymes; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D013925:Thromboplastin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000077466:Tirofiban