TY - JOUR
T1 - Role of thromboxane receptor in c-reactive protein-induced thrombosis
AU - Grad, Etty
AU - Pachino, Rachel M.
AU - Fitzgerald, Garret A.
AU - Danenberg, Haim D.
PY - 2012/10
Y1 - 2012/10
N2 - OBJECTIVE-: Thromboxane A2 and prostacyclin are thromboregulatory prostaglandins. The inflammatory C-reactive protein (CRP) promotes thrombosis after vascular injury, presumably via potentiation of thromboxane activity. Using a genetic approach, we investigated the role of thromboxane receptor (TP-/-) pathway in CRP-induced thrombosis. METHODS AND RESULTS-: Four genetically engineered mice strains were used: C57BL/6 wild-type, human CRP transgenic (CRPtg), thromboxane receptor-deficient (Tp-/-), and CRPtgTp-/- mice. CRP and TP-/- expression were correlated, and suppression of CRP expression using small interfering RNA/CRP led to reduction in TP-/- expression. Platelet-endothelial adherence was increased in CRPtg and suppressed in CRPtgTP-/- and CRPtg cells that were suppressed with TP-/- small interfering RNA. TP-/- deficiency in both platelets and endothelial cells was synergistic in affecting platelet-endothelial interactions. Time until arterial occlusion, measured after photochemical injury, was significantly shorter in CRPtg and prolonged in CRPtgTp-/- compared with controls (n=10-15, 35±3.4, 136±13.8, and 67±8.9 minutes, respectively; P<0.05). CONCLUSION-: TP-/- pathway is of major importance in CRP-induced thrombosis. The expression of TP-/- is increased in CRPtg endothelial cells, and its blockade significantly suppresses the prothrombotic effect of CRP.
AB - OBJECTIVE-: Thromboxane A2 and prostacyclin are thromboregulatory prostaglandins. The inflammatory C-reactive protein (CRP) promotes thrombosis after vascular injury, presumably via potentiation of thromboxane activity. Using a genetic approach, we investigated the role of thromboxane receptor (TP-/-) pathway in CRP-induced thrombosis. METHODS AND RESULTS-: Four genetically engineered mice strains were used: C57BL/6 wild-type, human CRP transgenic (CRPtg), thromboxane receptor-deficient (Tp-/-), and CRPtgTp-/- mice. CRP and TP-/- expression were correlated, and suppression of CRP expression using small interfering RNA/CRP led to reduction in TP-/- expression. Platelet-endothelial adherence was increased in CRPtg and suppressed in CRPtgTP-/- and CRPtg cells that were suppressed with TP-/- small interfering RNA. TP-/- deficiency in both platelets and endothelial cells was synergistic in affecting platelet-endothelial interactions. Time until arterial occlusion, measured after photochemical injury, was significantly shorter in CRPtg and prolonged in CRPtgTp-/- compared with controls (n=10-15, 35±3.4, 136±13.8, and 67±8.9 minutes, respectively; P<0.05). CONCLUSION-: TP-/- pathway is of major importance in CRP-induced thrombosis. The expression of TP-/- is increased in CRPtg endothelial cells, and its blockade significantly suppresses the prothrombotic effect of CRP.
KW - C-reactive protein
KW - endothelium
KW - platelets
KW - thrombosis
KW - thromboxane receptor
UR - http://www.scopus.com/inward/record.url?scp=84866617133&partnerID=8YFLogxK
U2 - 10.1161/atvbaha.112.256073
DO - 10.1161/atvbaha.112.256073
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 22879580
AN - SCOPUS:84866617133
SN - 1079-5642
VL - 32
SP - 2468
EP - 2474
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 10
ER -