Abstract P318: Vasoprotective Effects of an Apo A-I Mimetic Peptide

Hepatic ischemia/reperfusion (I/R) injury is associated with several pathologic states and contributes to the development of systemic vascular complications. High density lipoprotein (HDL) and apolipoprotein (apo) A-1 possess antioxidant and anti-inflammatory properties and reduce tissue injury in several models of I/R. In the current study, we tested the hypothesis that the synthetic apoA-I mimetic peptide 4F, similar to HDL and apoA-I, exerts cytoprotective effects in a murine model of hepatic I/R injury. C57BL/6 mice were randomized to receive 4F (5 mg/kg, IP) or an equivalent volume of saline vehicle. Mice were then subjected to 45 min of segmental hepatic ischemia, followed by 24 hr reperfusion. Sham-operated mice served as a control. Hepatic I/R injury was associated with an increase in alanine transaminase (ALT: 980±95U/mL) and xanthine oxidase (XO: 700±100U/mL) release compared to sham-operated controls (ALT=27±8U/mL; XO=100±10U/mL). Endothelium-dependent relaxation was impaired in aortae of I/R mice (R max =20%) compared to controls (R max =72%). This response was associated with a decrease in eNOS protein and an increase in iNOS and plasma levels of nitric oxide metabolites (NOx). Further, immunohistochemical studies revealed an increase in the nitration (3-NT) and chlorination (3-CT) of protein tyrosine residues in aortic sections from I/R mice that was associated with an increase in tissue myeloperoxidase (MPO) content. 4F treatment significantly improved the relaxation response in the aorta of I/R mice (R max =60%), prevented the upregulation of iNOS and NOx and reduced tissue protein nitration/chlorination. 4F treatment was further associated with a reduction in hepatocellular injury in I/R mice, as revealed by a decrease in ALT (110±15U/mL) and XO (270±50U/mL) release. Collectively, these data suggest that 4F reduces systemic vascular injury via cytoprotective effects at the level of the liver. ApoA-I mimetic peptide-based therapies may be effective in reducing vascular complications associated with clinical procedures such as transplantation.