Molecular mechanisms of platelet-mediated leukocyte recruitment during myocardial reperfusion.
Leukocyte interaction with platelets and endothelial cells as cause of myocardial stunning was investigated. Mice were anesthetized and, after thoracotomy, the LAD was ligated for 20 min. Where indicated, rhodamine 6G for leukocyte labeling, fluorescence-labeled platelets, and the GPIIb/IIIa antagonist Tirofiban were infused at the onset of reperfusion in vivo. After 15 min, hearts were quickly excised and analyzed by fluorescence microscopy or assessed for left ventricular developed pressure (LVDP). After in vivo ischemia and reperfusion, leukocyte retention in the heart was 55 +/- 5/field in wild-type hearts, 38 +/- 3/field in P-selectin-/- hearts, and 23 +/- 4/field in P-selectin/intercellular adhesion molecule-1 (ICAM-1)-/- hearts. Postischemic LVDP (48+/-4 mmHg in wild-type hearts) improved in P-selectin-/- and P-selectin/ICAM-1-/- hearts (58+/-4 and 79+/-6 mmHg). Tirofiban reduced platelet adhesion (23+/-4/field vs. 61+/-2/field in wild-type hearts) and leukocyte recruitment (34+/-2/field), improving LVDP (63+/-4 mmHg). Whereas wild-type platelets displayed similar adherence to P-selectin/ICAM-1-/- hearts as platelets from the same genetic strain (63+/-3 vs. 61+/-4 platelets/field), wild-type platelet infusion restored postischemic leukocyte recruitment in P-selectin/ICAM-1-/- hearts (55+/-4/field vs. 23+/-4/field), an effect sensitive to Tirofiban inhibition (23+/-4 leukocytes/field, 22+/-3 platelets/field). We conclude that platelets contribute postischemic leukocyte adhesion in the heart via P-selectin and GPIIb/IIIa.
Kupatt
Christian
C
Internal Medicine I, Klinikum Grosshadern, Munich, Germany.
Wichels
Reinhard
R
Horstkotte
Jan
J
Krombach
Fritz
F
Habazettl
Helmut
H
Boekstegers
Peter
P
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D003331:Coronary Vessels; D004730:Endothelium, Vascular / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000276:immunology / Q000473:pathology; D015425:Myocardial Reperfusion; D019007:P-Selectin / Q000502:physiology; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000502:physiology; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016277:Ventricular Function, Left
D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D018799:Intercellular Adhesion Molecule-1; D014443:Tyrosine; D000077466:Tirofiban