Rapamycin attenuates liver graft injury in cirrhotic recipient--the significance of down-regulation of Rho-ROCK-VEGF pathway.
To investigate whether rapamycin could attenuate hepatic I/R injury in a cirrhotic rat liver transplantation model, we applied a rat orthotopic liver transplantation model using 100% or 50% of liver grafts and cirrhotic recipients. Rapamycin was given (0.2 mg/kg, i.v.) at 30 min before graft harvesting in the donor and 24 h before operation, 30 min before total hepatectomy and immediately after reperfusion in the recipient. Rapamycin significantly improved small-for-size graft survival from 8.3% (1/12) to 66.7% (8/12) (p = 0.027). It also increased 7-day survival rates of whole grafts (58.3%[7/12] vs. 83.3%[10/12], p = 0.371). Activation of hepatic stellate cells was mainly found in small-for-size grafts during the first 7 days after liver transplantation. Rapamycin suppressed expression of smooth muscle actin, which is a marker of hepatic stellate cell activation, especially in small-for-size grafts. Intragraft protein expression and mRNA levels of vascular endothelial growth factor (VEGF) were down-regulated by rapamycin at 48 h both in whole and small-for-size grafts. Consistently, mRNA levels and protein expression of Rho and ROCK I were decreased by rapamycin during the 48 h after liver transplantation. In conclusion, rapamycin attenuated graft injury in a cirrhotic rat liver transplantation model by suppression of hepatic stellate cell activation, related to down-regulation of Rho-ROCK-VEGF pathway.
Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong. kwanman@hkucc.hku.hk
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D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects* / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000601:surgery*; D016031:Liver Transplantation; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases
D000199:Actins; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus; D042461:Vascular Endothelial Growth Factor A; D020741:rho GTP-Binding Proteins; D054460:rho-Associated Kinases; C498862:Acta2 protein, rat