Simvastatin potentiates tumor necrosis factor α-mediated apoptosis of human vascular endothelial cells via the inhibition of the geranylgeranylation of RhoA

Dongjiang Tang, Ho Jin Park, Serban P. Georgescu, Saïd M. Sebti, Andrew Hamilton, Jonas B. Galper

Research output: Contribution to journalArticle

Abstract

HMG-CoA reductase inhibitors (statins) are widely used in the treatment and prevention of atherosclerosis. Here we demonstrate that the HMG-CoA reductase inhibitor simvastatin potentiates TNFα-mediated apoptosis and TNFα signaling in human umbilical vein endothelial cells (HUVECs). While 2.5 μM simvastatin or 40 ng/ml TNFα alone had only a small effect on apoptosis in HUVECs, co-incubation with simvastatin and TNFα markedly increased apoptosis in a time- and dose-dependent manner as measured by FACS analysis of propidium iodide-stained cells. Geranylgeraniol, which serves as a substrate for the geranylgeranylation of small GTP binding proteins such as RhoA, which is required for the function and membrane localization of Rho, reversed the effect of simvastatin on apoptosis. GGTI, an inhibitor of protein geranylgeranylation, mimicked the effect of simvastatin on apoptosis and interfered with the membrane localization of RhoA. Furthermore, simvastatin increased the expression of the TNFα type I receptor (TNFαRI) with a dose dependence and a dependence on geranylgeranylation similar to that demonstrated for the potentiation of TNFα-mediated apoptosis. Adenoviral expression of a dominant-negative RhoA mimicked the effect of simvastatin on the expression of TNFαRI, while adenoviral expression of a dominant-activating RhoA mutant reversed the effect of simvastatin on the expression of TNFαRI. Simvastatin also potentiated TNFα signaling as determined by increased TNFα-mediated E-selectin expression. These data support the conclusion that TNFα signaling is under the negative control of RhoA and that statins potentiate TNFα signaling at least in part via interference with RhoA inhibition of TNFα type I receptor expression.

Original languageEnglish (US)
Pages (from-to)1484-1492
Number of pages9
JournalLife Sciences
Volume79
Issue number15
DOIs
StatePublished - Sep 5 2006

Fingerprint

Prenylation
Simvastatin
Endothelial cells
Endothelial Cells
Tumor Necrosis Factor-alpha
Apoptosis
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Tumor Necrosis Factor Receptors
Human Umbilical Vein Endothelial Cells
Protein Prenylation
Membranes
E-Selectin
Propidium
GTP-Binding Proteins
Atherosclerosis

Keywords

  • Anti-tumor effects
  • Apoptosis
  • Geranylgeranylation
  • RhoA
  • Statins

ASJC Scopus subject areas

  • Pharmacology

Cite this

Simvastatin potentiates tumor necrosis factor α-mediated apoptosis of human vascular endothelial cells via the inhibition of the geranylgeranylation of RhoA. / Tang, Dongjiang; Park, Ho Jin; Georgescu, Serban P.; Sebti, Saïd M.; Hamilton, Andrew; Galper, Jonas B.

In: Life Sciences, Vol. 79, No. 15, 05.09.2006, p. 1484-1492.

Research output: Contribution to journalArticle

Tang, Dongjiang ; Park, Ho Jin ; Georgescu, Serban P. ; Sebti, Saïd M. ; Hamilton, Andrew ; Galper, Jonas B. / Simvastatin potentiates tumor necrosis factor α-mediated apoptosis of human vascular endothelial cells via the inhibition of the geranylgeranylation of RhoA. In: Life Sciences. 2006 ; Vol. 79, No. 15. pp. 1484-1492.
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T1 - Simvastatin potentiates tumor necrosis factor α-mediated apoptosis of human vascular endothelial cells via the inhibition of the geranylgeranylation of RhoA

AU - Tang, Dongjiang

AU - Park, Ho Jin

AU - Georgescu, Serban P.

AU - Sebti, Saïd M.

AU - Hamilton, Andrew

AU - Galper, Jonas B.

PY - 2006/9/5

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N2 - HMG-CoA reductase inhibitors (statins) are widely used in the treatment and prevention of atherosclerosis. Here we demonstrate that the HMG-CoA reductase inhibitor simvastatin potentiates TNFα-mediated apoptosis and TNFα signaling in human umbilical vein endothelial cells (HUVECs). While 2.5 μM simvastatin or 40 ng/ml TNFα alone had only a small effect on apoptosis in HUVECs, co-incubation with simvastatin and TNFα markedly increased apoptosis in a time- and dose-dependent manner as measured by FACS analysis of propidium iodide-stained cells. Geranylgeraniol, which serves as a substrate for the geranylgeranylation of small GTP binding proteins such as RhoA, which is required for the function and membrane localization of Rho, reversed the effect of simvastatin on apoptosis. GGTI, an inhibitor of protein geranylgeranylation, mimicked the effect of simvastatin on apoptosis and interfered with the membrane localization of RhoA. Furthermore, simvastatin increased the expression of the TNFα type I receptor (TNFαRI) with a dose dependence and a dependence on geranylgeranylation similar to that demonstrated for the potentiation of TNFα-mediated apoptosis. Adenoviral expression of a dominant-negative RhoA mimicked the effect of simvastatin on the expression of TNFαRI, while adenoviral expression of a dominant-activating RhoA mutant reversed the effect of simvastatin on the expression of TNFαRI. Simvastatin also potentiated TNFα signaling as determined by increased TNFα-mediated E-selectin expression. These data support the conclusion that TNFα signaling is under the negative control of RhoA and that statins potentiate TNFα signaling at least in part via interference with RhoA inhibition of TNFα type I receptor expression.

AB - HMG-CoA reductase inhibitors (statins) are widely used in the treatment and prevention of atherosclerosis. Here we demonstrate that the HMG-CoA reductase inhibitor simvastatin potentiates TNFα-mediated apoptosis and TNFα signaling in human umbilical vein endothelial cells (HUVECs). While 2.5 μM simvastatin or 40 ng/ml TNFα alone had only a small effect on apoptosis in HUVECs, co-incubation with simvastatin and TNFα markedly increased apoptosis in a time- and dose-dependent manner as measured by FACS analysis of propidium iodide-stained cells. Geranylgeraniol, which serves as a substrate for the geranylgeranylation of small GTP binding proteins such as RhoA, which is required for the function and membrane localization of Rho, reversed the effect of simvastatin on apoptosis. GGTI, an inhibitor of protein geranylgeranylation, mimicked the effect of simvastatin on apoptosis and interfered with the membrane localization of RhoA. Furthermore, simvastatin increased the expression of the TNFα type I receptor (TNFαRI) with a dose dependence and a dependence on geranylgeranylation similar to that demonstrated for the potentiation of TNFα-mediated apoptosis. Adenoviral expression of a dominant-negative RhoA mimicked the effect of simvastatin on the expression of TNFαRI, while adenoviral expression of a dominant-activating RhoA mutant reversed the effect of simvastatin on the expression of TNFαRI. Simvastatin also potentiated TNFα signaling as determined by increased TNFα-mediated E-selectin expression. These data support the conclusion that TNFα signaling is under the negative control of RhoA and that statins potentiate TNFα signaling at least in part via interference with RhoA inhibition of TNFα type I receptor expression.

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