Disinhibition of SOD-2 expression to compensate for a genetically determined NO deficit in endothelial cells--brief report.
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.


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 (O(2)(-)) 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.
Asif
Abdul R
AR
Department of Clinical Chemistry, University Medicine Göttingen, Germany.
Hecker
Markus
M
Cattaruzza
Marco
M
D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D013058:Mass Spectrometry; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D000099156:Superoxide Dismutase 2
D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C496314:NOS3 protein, human