Aortic eNOS expression and phosphorylation in Apo-E knockout mice: Differing effects of rapamycin and simvastatin

Joseph J. Naoum, Shu Zhang, Kenneth J. Woodside, Wei Song, Qian Guo, Ligia Belalcazar, Glenn C. Hunter

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background The inhibition of nitric oxide (NO) by hypercholesterolemia may be mediated, in part, by interactions with caveolin-1 (Cav-1). Because of the facilitatory effects of statins on endothelial function and the adverse effects of rapamycin (RAPA) on plasma lipids, we compared the effects of simvastatin (SMV) and RAPA on endothelial NO synthase (eNOS) and Cav-1 protein expression and phosphorylation in the aortas of apolipoprotein E (Apo-E) knockout (-/-) mice. Methods Apo-E -/- mice (n=38) fed a high-cholesterol diet were given SMV (100 mg/kg/day po), RAPA (3 mg/kg/day ip), or no treatment for 10 weeks. Blood was drawn for serum lipid analysis, and protein was extracted for Western immunoblotting. Selected aortic specimens from 2 animals in each group were examined by histology and immunohistochemistry. The data are expressed as the mean ± SEM and compared by the Student t test and ANOVA. Significance was established as P < .05. Results Lipid levels at 10 weeks were similar in the 3 groups except for higher triglyceride levels in RAPA-treated animals. eNOS expression was highest in RAPA-treated mice, but the p-eNOS to eNOS protein expression ratio was significantly greater in the SMV treatment group compared to both RAPA and controls (P < .05). Both Cav-1 and p-Cav-1 expression was significantly lower in the SMV-treated animals (P < .05) compared to mice treated with RAPA. Conclusions Although eNOS expression was greatest in the RAPA-treated mice, the expression of p-eNOS was similar in the RAPA- and SMV-treated animals. The increase in eNOS induced by RAPA and the inverse relationship between p-eNOS and Cav-1 protein expression observed with SMV treatment suggest different mechanisms for the regulation of aortic eNOS expression in Apo-E mice by these 2 agents.

Original languageEnglish (US)
Pages (from-to)323-328
Number of pages6
JournalSurgery
Volume136
Issue number2
DOIs
StatePublished - Aug 2004

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Simvastatin
Apolipoproteins E
Sirolimus
Knockout Mice
Nitric Oxide Synthase
Phosphorylation
Caveolin 1
Caveolins
Lipids
Apolipoprotein E2
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Nitric Oxide Synthase Type III
Hypercholesterolemia
Aorta
Histology
Analysis of Variance
Nitric Oxide
Triglycerides
Proteins
Therapeutics

ASJC Scopus subject areas

  • Surgery

Cite this

Aortic eNOS expression and phosphorylation in Apo-E knockout mice : Differing effects of rapamycin and simvastatin. / Naoum, Joseph J.; Zhang, Shu; Woodside, Kenneth J.; Song, Wei; Guo, Qian; Belalcazar, Ligia; Hunter, Glenn C.

In: Surgery, Vol. 136, No. 2, 08.2004, p. 323-328.

Research output: Contribution to journalArticle

Naoum, Joseph J. ; Zhang, Shu ; Woodside, Kenneth J. ; Song, Wei ; Guo, Qian ; Belalcazar, Ligia ; Hunter, Glenn C. / Aortic eNOS expression and phosphorylation in Apo-E knockout mice : Differing effects of rapamycin and simvastatin. In: Surgery. 2004 ; Vol. 136, No. 2. pp. 323-328.
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abstract = "Background The inhibition of nitric oxide (NO) by hypercholesterolemia may be mediated, in part, by interactions with caveolin-1 (Cav-1). Because of the facilitatory effects of statins on endothelial function and the adverse effects of rapamycin (RAPA) on plasma lipids, we compared the effects of simvastatin (SMV) and RAPA on endothelial NO synthase (eNOS) and Cav-1 protein expression and phosphorylation in the aortas of apolipoprotein E (Apo-E) knockout (-/-) mice. Methods Apo-E -/- mice (n=38) fed a high-cholesterol diet were given SMV (100 mg/kg/day po), RAPA (3 mg/kg/day ip), or no treatment for 10 weeks. Blood was drawn for serum lipid analysis, and protein was extracted for Western immunoblotting. Selected aortic specimens from 2 animals in each group were examined by histology and immunohistochemistry. The data are expressed as the mean ± SEM and compared by the Student t test and ANOVA. Significance was established as P < .05. Results Lipid levels at 10 weeks were similar in the 3 groups except for higher triglyceride levels in RAPA-treated animals. eNOS expression was highest in RAPA-treated mice, but the p-eNOS to eNOS protein expression ratio was significantly greater in the SMV treatment group compared to both RAPA and controls (P < .05). Both Cav-1 and p-Cav-1 expression was significantly lower in the SMV-treated animals (P < .05) compared to mice treated with RAPA. Conclusions Although eNOS expression was greatest in the RAPA-treated mice, the expression of p-eNOS was similar in the RAPA- and SMV-treated animals. The increase in eNOS induced by RAPA and the inverse relationship between p-eNOS and Cav-1 protein expression observed with SMV treatment suggest different mechanisms for the regulation of aortic eNOS expression in Apo-E mice by these 2 agents.",
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T2 - Differing effects of rapamycin and simvastatin

AU - Naoum, Joseph J.

AU - Zhang, Shu

AU - Woodside, Kenneth J.

AU - Song, Wei

AU - Guo, Qian

AU - Belalcazar, Ligia

AU - Hunter, Glenn C.

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N2 - Background The inhibition of nitric oxide (NO) by hypercholesterolemia may be mediated, in part, by interactions with caveolin-1 (Cav-1). Because of the facilitatory effects of statins on endothelial function and the adverse effects of rapamycin (RAPA) on plasma lipids, we compared the effects of simvastatin (SMV) and RAPA on endothelial NO synthase (eNOS) and Cav-1 protein expression and phosphorylation in the aortas of apolipoprotein E (Apo-E) knockout (-/-) mice. Methods Apo-E -/- mice (n=38) fed a high-cholesterol diet were given SMV (100 mg/kg/day po), RAPA (3 mg/kg/day ip), or no treatment for 10 weeks. Blood was drawn for serum lipid analysis, and protein was extracted for Western immunoblotting. Selected aortic specimens from 2 animals in each group were examined by histology and immunohistochemistry. The data are expressed as the mean ± SEM and compared by the Student t test and ANOVA. Significance was established as P < .05. Results Lipid levels at 10 weeks were similar in the 3 groups except for higher triglyceride levels in RAPA-treated animals. eNOS expression was highest in RAPA-treated mice, but the p-eNOS to eNOS protein expression ratio was significantly greater in the SMV treatment group compared to both RAPA and controls (P < .05). Both Cav-1 and p-Cav-1 expression was significantly lower in the SMV-treated animals (P < .05) compared to mice treated with RAPA. Conclusions Although eNOS expression was greatest in the RAPA-treated mice, the expression of p-eNOS was similar in the RAPA- and SMV-treated animals. The increase in eNOS induced by RAPA and the inverse relationship between p-eNOS and Cav-1 protein expression observed with SMV treatment suggest different mechanisms for the regulation of aortic eNOS expression in Apo-E mice by these 2 agents.

AB - Background The inhibition of nitric oxide (NO) by hypercholesterolemia may be mediated, in part, by interactions with caveolin-1 (Cav-1). Because of the facilitatory effects of statins on endothelial function and the adverse effects of rapamycin (RAPA) on plasma lipids, we compared the effects of simvastatin (SMV) and RAPA on endothelial NO synthase (eNOS) and Cav-1 protein expression and phosphorylation in the aortas of apolipoprotein E (Apo-E) knockout (-/-) mice. Methods Apo-E -/- mice (n=38) fed a high-cholesterol diet were given SMV (100 mg/kg/day po), RAPA (3 mg/kg/day ip), or no treatment for 10 weeks. Blood was drawn for serum lipid analysis, and protein was extracted for Western immunoblotting. Selected aortic specimens from 2 animals in each group were examined by histology and immunohistochemistry. The data are expressed as the mean ± SEM and compared by the Student t test and ANOVA. Significance was established as P < .05. Results Lipid levels at 10 weeks were similar in the 3 groups except for higher triglyceride levels in RAPA-treated animals. eNOS expression was highest in RAPA-treated mice, but the p-eNOS to eNOS protein expression ratio was significantly greater in the SMV treatment group compared to both RAPA and controls (P < .05). Both Cav-1 and p-Cav-1 expression was significantly lower in the SMV-treated animals (P < .05) compared to mice treated with RAPA. Conclusions Although eNOS expression was greatest in the RAPA-treated mice, the expression of p-eNOS was similar in the RAPA- and SMV-treated animals. The increase in eNOS induced by RAPA and the inverse relationship between p-eNOS and Cav-1 protein expression observed with SMV treatment suggest different mechanisms for the regulation of aortic eNOS expression in Apo-E mice by these 2 agents.

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