A cardioprotective role for the endothelial protein C receptor in lipopolysaccharide-induced endotoxemia in the mouse.
A model of gram-negative lethal endotoxin shock, involving continuous peritoneal infusion of lipopolysaccharide (LPS), has been applied to wild-type (WT) mice and mice with a severe deficiency of endothelial protein C receptor (EPCR(delta/delta)). The survival of EPCR(delta/delta) mice was significantly diminished as compared to WT mice after administration of LPS via this route. Heart rates and central blood pressures also were significantly more depressed in EPCR(delta/delta) mice, indicating that the receptor-based protein C (PC) pathway functions in regulation of hemodynamic properties in the mouse. Further, heart muscle damage was more severe in EPCR(delta/delta) mice as compared to WT mice after endotoxin administration, as revealed by the more elevated plasma myoglobin levels in EPCR(delta/delta) mice and by microscopic examination of stained heart sections. Neutrophil infiltration was more pronounced in heart tissue of EPCR(delta/delta) mice, perhaps in response to the greatly increased expression level of the chemokine, MIP-2, which also significantly more up-regulated in the LPS-treated EPCR(delta/delta) mouse cohort. In conclusion, a severe deficiency of EPCR adversely affects survival of mice subjected to continuous infusion of endotoxin, via contributions of more responsive hemodynamic and cardiac alterations, thus suggesting that, among its other functions, the PC-based receptor system has a cardioprotective role after acute inflammatory challenge.
Iwaki
Takayuki
T
W. M. Keck Center for Transgene Research, Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Cruz
Diana T
DT
Martin
J Andrew
JA
Castellino
Francis J
FJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D000074283:Endothelial Protein C Receptor; D019446:Endotoxemia / Q000097:blood* / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D006023:Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009211:Myoglobin / Q000097:blood; D020556:Neutrophil Infiltration / Q000235:genetics; D011956:Receptors, Cell Surface; D012772:Shock, Septic / Q000097:blood* / Q000139:chemically induced / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D000074283:Endothelial Protein C Receptor; D006023:Glycoproteins; D008070:Lipopolysaccharides; D009211:Myoglobin; C080248:Procr protein, mouse; D011956:Receptors, Cell Surface