From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular
Division, Department of Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, Mass.
Correspondence to James K. Liao, MD, Vascular Medicine and Atherosclerosis Unit, Brigham and Women's Hospital, 221 Longwood Ave, LMRC-316, Boston, MA 02115. E-mail jkliao{at}bics.bwh.harvard.edu
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 (
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.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Upregulation of Endothelial Nitric Oxide Synthase by HMG CoA Reductase Inhibitors
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.
Key Words: atherosclerosis • endothelium-derived factors • lipoproteins • genes
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