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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2642.)
© 2007 American Heart Association, Inc.

Vascular Biology

Statin Treatment and 3' Polyadenylation of eNOS mRNA

Ioanna Kosmidou; Jeffrey P. Moore; Martina Weber; Charles D. Searles

From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga.

Correspondence to Charles D. Searles, MD, Division of Cardiology, Emory University School of Medicine, 1639 Pierce Dr, WMB 319, Atlanta, GA 30322. E-mail csearle{at}emory.edu

Objective— Statins have been shown to increase endothelial nitric oxide synthase expression via enhanced mRNA stability. Because the poly(A) tail is an important determinant of transcript stability, we sought to characterize the effect of statins on eNOS mRNA 3' polyadenylation.

Methods and Results— Endothelial cells treated with statins had a time- and dose-dependent increase in eNOS transcripts with long poly(A) tails (75 to 160 adenosines). This effect was dependent on 3-hydroxy-3-methylglutaryl (HMG)-coenxyme A (CoA) reductase inhibition and was observed with both lipophilic (simvastatin) and hydrophilic (rosuvastatin) statins. In mRNA stability assays, polyadenylated eNOS transcripts from statin-treated cells were 2- to 3-fold more stable than transcripts from untreated cells. The effect of statins on eNOS polyadenylation was related to cytoskeleton organization; there was increased eNOS mRNA polyadenylation after Rho inhibition and cytochalasin D treatment. Further, we found increased phosphorylation of RNA polymerase II in statin-treated cells, suggesting that statin-induced polyadenylation involved modulation of RNA polymerase II activity.

Conclusions— Our data provide insight into a mechanism by which statins enhance eNOS mRNA stability and increase eNOS protein: statins increase eNOS mRNA polyadenylation through Rho-mediated changes in the actin cytoskeleton.

We examined the effect of statins on eNOS mRNA polyadenylation, a process known to increase mRNA stability and translation. Statins increased polyadenylation in a time- and dose-dependent manner through a mechanism that appears to involve Rho-induced changes in the actin cytoskeleton.

Key Words: endothelial nitric oxide synthase • mRNA stability • polyadenylation • posttranscriptional regulation • statin

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