Upregulation of Endothelial Nitric Oxide Synthase by HMG CoA Reductase Inhibitors

Author:

Laufs Ulrich1,La Fata Vito1,Plutzky Jorge1,Liao James K.1

Affiliation:

1. From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

Abstract

Background —Oxidized low-density lipoprotein (ox-LDL) causes endothelial dysfunction in part by decreasing the availability of endothelial nitric oxide (NO). Although HMG CoA reductase inhibitors restore endothelial function by reducing serum cholesterol levels, it is not known whether they can also directly upregulate endothelial NO synthase (ecNOS) activity. Methods and Results —Human saphenous vein endothelial cells were treated with ox-LDL (50 μg/mL thiobarbituric acid reactive substances 12 to 16 nmol/mg) in the presence of HMG CoA reductase inhibitors simvastatin and lovastatin. In a time-dependent manner, ox-LDL decreased ecNOS mRNA and protein levels (91±4% and 67±8% reduction after 72 hours, respectively). Both simvastatin (1 μmol/L) and lovastatin (10 μmol/L) upregulated ecNOS expression by 3.8-fold and 3.6-fold, respectively, and completely prevented its downregulation by ox-LDL. These effects of simvastatin on ecNOS expression correlated with changes in ecNOS activity. Although l -mevalonate alone did not affect ecNOS expression, cotreatment with l -mevalonate completely reversed ecNOS upregulation by simvastatin. Actinomycin D studies revealed that simvastatin stabilized ecNOS mRNA (τ 1/2 , 43 versus 35 hours). Nuclear run-on assays and transient transfection studies with a −1.6 kb ecNOS promoter construct showed that simvastatin did not affect ecNOS gene transcription. Conclusions —Inhibition of endothelial HMG CoA reductase upregulates ecNOS expression predominantly by posttranscriptional mechanisms. These findings suggest that HMG CoA reductase inhibitors may have beneficial effects in atherosclerosis beyond that attributed to the lowering of serum cholesterol by increasing ecNOS activity.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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