doi: 10.1161/hc4001.097056
(Circulation. 2001;104:1767.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Induction of NAD(P)H Oxidase by Oxidized Low-Density Lipoprotein in Human Endothelial Cells
Antioxidative Potential of Hydroxymethylglutaryl Coenzyme A Reductase Inhibitor Therapy
From the Institute of Pathophysiology (U.R., J.H., H.M.), the Julius-Bernstein-Institute of Physiology (U.R.), and the Clinic for Cardiothoracic Surgery (H.-R.Z.), Martin Luther University Halle-Wittenberg, Halle, Germany; the Clinic for Internal Medicine, University of Wuerzburg, Germany (J.G.); and the Division of Cardiothoracic Surgery (H.-R.Z.), University of Basel, Kantonspital, Basel, Switzerland.
Correspondence to Henning Morawietz, PhD, Institute of Pathophysiology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Magdeburger Straße 18, D-06097 Halle, Germany. E-mail henning.morawietz{at}medizin.uni-halle.de
Background— Elevated oxidative stress and superoxide anion formation in vascular cells could promote conversion of LDL to atherogenic oxidized LDL (oxLDL), contributing to endothelial dysfunction and atherosclerosis. As a major source of vascular superoxide anion formation, an endothelial NAD(P)H oxidase, similar to the leukocyte enzyme, has been identified.
Methods and Results— To elucidate functional differences between NAD(P)H oxidases of endothelial cells and leukocytes, DNA sequences of endothelial NAD(P)H oxidase subunits were determined. Gp91phox cDNA sequence showed no difference between the 2 cell types. Endothelial p67phox cDNA sequence revealed 2 known polymorphisms, which do not affect NAD(P)H oxidase function. Next, we analyzed relative mRNA expression of NAD(P)H subunits in human umbilical vein endothelial cells (HUVECs) and leukocytes using a common cRNA standard in competitive reverse transcription–polymerase chain reaction. NAD(P)H oxidase subunits p22phox and p47phox are expressed at a similar level in both cell types, whereas p67phox (2.5%) and gp91phox (1.1%) are expressed at a much lower level in endothelial cells than in leukocytes. Differences of gp91phox expression in leukocytes and HUVECs correlate with differences in superoxide release. Gp91phox mRNA and endothelial superoxide anion formation are induced in response to oxLDL in HUVECs. Furthermore, a lower gp91phox mRNA expression was found in internal mammary artery biopsy samples of patients with coronary artery disease treated with HMG-CoA reductase inhibitors before coronary bypass surgery.
Conclusions— We conclude that oxLDL induces proatherosclerotic NAD(P)H oxidase expression and superoxide anion formation in human endothelial cells and an antioxidative potential of HMG-CoA reductase inhibition via reduction of vascular NAD(P)H oxidase expression.
Key Words: atherosclerosis • endothelium • free radicals • lipoproteins
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