3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors decrease Fas ligand expression and cytotoxicity in
Luis Miguel Blanco-Colio1, Begoña Muñoz-García, Jose Luis Martín-Ventura
1Vascular Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
Insights
Statins like atorvastatin reduce T cell FasL expression and cytotoxicity, likely by inhibiting RhoA prenylation. This mechanism may explain how statins reduce atherosclerotic plaque cell content.
Area of Science:
- Cardiovascular Research
- Immunology
- Molecular Biology
Background:
- HMG-CoA reductase inhibitors (statins) reduce cardiovascular mortality through incompletely understood mechanisms.
- T cells and apoptotic cells are present in atherosclerotic plaques, with reduced cellularity indicating plaque stability.
- The Fas-Fas ligand (FasL) system is a key pathway for T cell-mediated apoptosis.
Purpose of the Study:
- To investigate whether HMG-CoA reductase inhibitors regulate FasL expression and cytotoxicity in human T cells.
- To elucidate the molecular mechanisms underlying statin-mediated regulation of FasL expression.
Main Methods:
- Human T cells (Jurkat cells) were activated and treated with atorvastatin or simvastatin.
- The role of protein prenylation and Rho GTPases in FasL expression was assessed using mevalonate, geranylgeranylpyrophosphate, farnesylpyrophosphate, and C3 exotoxin.
- RhoA signaling was manipulated using constitutively active and dominant-negative constructs.
- Cytotoxic activity was measured using FasL-sensitive target cells.
- FasL expression was also analyzed in peripheral blood mononuclear cells and human carotid atherosclerotic plaques.
Main Results:
- Atorvastatin and simvastatin prevented the increase in FasL expression on activated T cells.
- Protein geranylation, specifically geranylgeranylation, and RhoA signaling were implicated in T cell FasL expression.
- Atorvastatin reduced the cytotoxic activity of activated T cells.
- Atorvastatin decreased FasL expression in peripheral blood mononuclear cells and atherosclerotic plaques.
Conclusions:
- Atorvastatin regulates FasL expression in T cells, likely via inhibition of RhoA prenylation.
- These findings suggest a novel mechanism by which atorvastatin influences T cell cytotoxicity and cellular content within atherosclerotic plaques.
Background:
HMG-CoA reductase inhibitors reduce cardiovascular mortality, although the mechanisms of action have not been completely elucidated. The presence of T cells and apoptotic cells in atherosclerotic plaques is well established, the reduction of cellular content being a marker of their vulnerability. One of the main mechanisms of cell death activation is the Fas-Fas ligand (FasL) system.
Methods And Results:
We studied whether HMG-CoA reductase inhibitors can regulate FasL expression and cytotoxicity in human T cells (Jurkat cells). Activation of Jurkat cells with phorbol esters and ionomycin increased FasL expression, an effect prevented by atorvastatin or simvastatin. Mevalonate and geranylgeranylpyrophosphate but not farnesylpyrophosphate prevented the effect of atorvastatin, indicating that protein geranylation was involved in FasL expression. The C3 exotoxin, which selectively inactivates Rho proteins, also decreased FasL expression on T cells. Overexpression of constitutively active RhoA increased FasL expression in Jurkat cells, and dominant-negative RhoA decreased FasL expression in activated cells, indicating that RhoA is implicated in FasL expression. Atorvastatin also decreased cytotoxic activity of activated Jurkat cells on FasL-sensitive cells. Finally, atorvastatin treatment reduced FasL expression in peripheral blood mononuclear cells and human carotid atherosclerotic plaques.
Conclusions:
Atorvastatin regulates FasL expression in T cells, probably because of the inhibition of RhoA prenylation. These results provide novel information by which atorvastatin may regulate the cytotoxic activity of T cells and the number of cells in the atherosclerotic plaque.
