(Circulation. 2000;102:3104.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Suppression of Endothelial Nitric Oxide Production After Withdrawal of Statin Treatment Is Mediated by Negative Feedback Regulation of Rho GTPase Gene Transcription
From the Medizinische Klinik und Poliklink, Universitatskliniken des Saarlandes, Homburg, Germany (U.L, F.C., G.N., M.B.); the Neurologische Klinik der Charite, Humboldt-Universität zu Berlin, Berlin, Germany (M.E., K.G.); and the Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (J.K.L.).
Correspondence to Ulrich Laufs, MD, Medizinische Klinik und Poliklink, Universitatskliniken des Saarlandes, Innere Medizin III, Homburg, 66421 Germany. E-mail Ulrich{at}Laufs.com
Background—Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function.
Methods and Results—To test this hypothesis, mice were treated for 14 days with 10 mg/kg atorvastatin per day; this led to the upregulation of endothelial NO synthase expression and activity by 2.3- and 3-fold, respectively. Withdrawal of statins resulted in a dramatic, 90% decrease of NO production after 2 days. In mouse aortas and cultured endothelial cells, statins upregulated the expression of rho GTPase in the cytosol, but statins blocked isoprenoid-dependent rho membrane translocation and GTP-binding activity. Inhibiting the downstream targets of rho showed that rho expression is controlled by a negative feedback mechanism mediated by the actin cytoskeleton. Measuring rho mRNA half-life and nuclear run-on assays demonstrated that statins or disruption of actin stress fibers increased rho gene transcription but not rho mRNA stability. Therefore, treatment with statins leads to the accumulation of nonisoprenylated rho in the cytosol. Withdrawing statin treatment restored the availability of isoprenoids and resulted in a massive membrane translocation and activation of rho, causing downregulation of endothelial NO production.
Conclusions—Withdrawal of statin therapy in normocholesterolemic mice results in a transient increase of rho activity, causing a suppression of endothelial NO production. The underlying molecular mechanism is a negative feedback regulation of rho gene transcription mediated by the actin cytoskeleton.
Key Words: nitric oxide • endothelium • statins • rho GTPase
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|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
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