TY - JOUR
T1 - Effects of rapamycin on the arterial inflammatory response in atherosclerotic plaques in Apo-E knockout mice
AU - Naoum, J. J.
AU - Woodside, K. J.
AU - Zhang, S.
AU - Rychahou, P. G.
AU - Hunter, G. C.
N1 - Funding Information:
Supported by the Sealy Center for Aging and the American Heart Association.
PY - 2005/5
Y1 - 2005/5
N2 - Because of its antiproliferative properties and its known effects on plasma lipids, we evaluated the mechanisms underlying the effect of rapamycin (RPM) on endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases in Apo-E knockout mice. Apo-E-/- mice fed a high-cholesterol diet were given RPM (3 mg/kg per day intraperitoneally) or no treatment for 10 weeks (n = 8 each). Blood was drawn for serum lipid analysis. Protein was extracted from the abdominal aortas for Western immunoblotting and zymography. Cellular localization was assessed by histology and immunohistochemistry. The data, expressed as mean ± SEM, were compared by Student's t test or analysis of variance (ANOVA). Lipid levels at 10 weeks were similar in both groups except for higher triglyceride levels in RPM-treated animals. RPM-treated mice expressed greater amounts of eNOS and p-eNOS compared with controls (P <. 05). Akt, p-Akt, Caveolin-1, and p-Caveolin-1 were not significantly affected by RPM treatment. RPM treatment was associated with increased activation of pro-MMP-9, a significant decrease in MMP-2 tissue levels, and corresponding increases in TIMP-2 and TIMP-3 expression. The increased expression and phosphorylation of eNOS with RPM appears to be regulated by mechanisms other than Akt or Caveolin-1. Alterations in eNOS expression, in addition to changes in MMP/TIMP ratios and MMP-2 and MMP-9 activation, may partially explain the changes observed in the aorta of treated Apo-E-/- mice induced by RPM.
AB - Because of its antiproliferative properties and its known effects on plasma lipids, we evaluated the mechanisms underlying the effect of rapamycin (RPM) on endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases in Apo-E knockout mice. Apo-E-/- mice fed a high-cholesterol diet were given RPM (3 mg/kg per day intraperitoneally) or no treatment for 10 weeks (n = 8 each). Blood was drawn for serum lipid analysis. Protein was extracted from the abdominal aortas for Western immunoblotting and zymography. Cellular localization was assessed by histology and immunohistochemistry. The data, expressed as mean ± SEM, were compared by Student's t test or analysis of variance (ANOVA). Lipid levels at 10 weeks were similar in both groups except for higher triglyceride levels in RPM-treated animals. RPM-treated mice expressed greater amounts of eNOS and p-eNOS compared with controls (P <. 05). Akt, p-Akt, Caveolin-1, and p-Caveolin-1 were not significantly affected by RPM treatment. RPM treatment was associated with increased activation of pro-MMP-9, a significant decrease in MMP-2 tissue levels, and corresponding increases in TIMP-2 and TIMP-3 expression. The increased expression and phosphorylation of eNOS with RPM appears to be regulated by mechanisms other than Akt or Caveolin-1. Alterations in eNOS expression, in addition to changes in MMP/TIMP ratios and MMP-2 and MMP-9 activation, may partially explain the changes observed in the aorta of treated Apo-E-/- mice induced by RPM.
UR - http://www.scopus.com/inward/record.url?scp=20344365093&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20344365093&partnerID=8YFLogxK
U2 - 10.1016/j.transproceed.2005.02.080
DO - 10.1016/j.transproceed.2005.02.080
M3 - Article
C2 - 15919492
AN - SCOPUS:20344365093
SN - 0041-1345
VL - 37
SP - 1880
EP - 1884
JO - Transplantation Proceedings
JF - Transplantation Proceedings
IS - 4
ER -