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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1890.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Disinhibition of SOD-2 Expression to Compensate for a Genetically Determined NO Deficit in Endothelial Cells–Brief Report

Abdul R. Asif; Markus Hecker; Marco Cattaruzza

From the Department of Clinical Chemistry (A.R.A.), University Medicine Göttingen, and the Institute of Physiology and Pathophysiology (M.H., M.C.), University of Heidelberg, Germany.

Correspondence to Dr Marco Cattaruzza, Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany. E-mail cattaruzza{at}physiologie.uni-heidelberg.de

Objective— Homozygosity for the –786C-variant of the human nos-3 gene is a risk factor for coronary artery disease (CAD). Interestingly, affected individuals develop CAD more frequently but not earlier than the general population.

Methods and Results— Genotyped primary human umbilical vein endothelial cells (ECs) were exposed to fluid shear stress (FSS) and analyzed for nitric oxide (NO) and superoxide anion (O₂^–) formation as well as mRNA and protein expression of different antioxidant enzymes. Dysfunctional CC-genotype ECs failed to upregulate NO synthase expression in response to FSS and exhibited a reduced NO synthesis capacity when compared to functionally intact TT-genotype ECs. However, only CC-genotype ECs responded to FSS with an Egr-1–mediated increase in manganese-containing superoxide dismutase (SOD-2) expression, shielding them from endothelin-1–induced oxidative stress in a NO-independent manner.

Conclusions— This FSS-induced rise in SOD-2 expression in CC-genotype ECs effectively stabilizes their antiatherosclerotic phenotype and may explain not only the comparatively slow onset of CAD in homozygous carriers of the C-allele of the nos-3 gene but also define a general strategy for preventing endothelial dysfunction at the outset of atherosclerosis.

Fluid shear stress–induced SOD-2 expression, mediated by the NO-sensitive activation of the transcription factor Egr-1, protects endothelial cells from oxidative stress, and may constitute a mechanism through which individuals homozygous for the –786C-variant of the nos-3 gene, despite an increased genetic risk, do not develop coronary artery disease early in life.

Key Words: endothelial function • nitric oxide • nitric oxide synthase • superoxide • SOD-2