Role of heme oxygenase-1 in human endothelial cells: lesson from the promoter allelic variants.
OBJECTIVE
Heme oxygenase-1 (HO-1) is an antioxidative, antiinflammatory, and cytoprotective enzyme that is induced in response to cellular stress. The HO-1 promoter contains a (GT)n microsatellite DNA, and the number of GT repeats can influence the occurrence of cardiovascular diseases. We elucidated the effect of this polymorphism on endothelial cells isolated from newborns of different genotypes.


RESULTS
On the basis of HO-1 expression, we classified the HO-1 promoter alleles into 3 groups: short (S) (most active, GT < or = 23), medium (moderately active, GT=24 to 28), and long (least active, GT > or = 29). The presence of the S allele led to higher basal HO-1 expression and stronger induction in response to cobalt protoporphyrin, prostaglandin-J(2), hydrogen peroxide, and lipopolysaccharide. Cells carrying the S allele survived better under oxidative stress, a fact associated with the lower concentration of oxidized glutathione and more favorable oxidative status, as determined by measurement of the ratio of glutathione to oxidized glutathione. Moreover, they proliferated more efficiently in response to vascular endothelial growth factor A, although the vascular endothelial growth factor-induced migration and sprouting of capillaries were not influenced. Finally, the presence of the S allele was associated with lower production of some proinflammatory mediators, such as interleukin-1beta, interleukin-6, and soluble intercellular adhesion molecule-1.


CONCLUSIONS
The (GT)n promoter polymorphism significantly modulates a cytoprotective, proangiogenic, and antiinflammatory function of HO-1 in human endothelium.
Department of Thoracic Surgery and Clinical Institute of Medical and Chemical Laboratory Diagnostics, University of Vienna, Austria.
Hevidar
H
Taha
Klaudia
K
Skrzypek
Ibeth
I
Guevara
Anneliese
A
Nigisch
Stefan
S
Mustafa
Anna
A
Grochot-Przeczek
Pawel
P
Ferdek
Halina
H
Was
Jerzy
J
Kotlinowski
Magdalena
M
Kozakowska
Aneta
A
Balcerczyk
Lucie
L
Muchova
Libor
L
Vitek
Guenter
G
Weigel
Jozef
J
Dulak
Alicja
A
Jozkowicz
D000483:Alleles; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D019610:Cytoprotection; D018900:Dinucleotide Repeats; D042783:Endothelial Cells / Q000201:enzymology* / Q000276:immunology; D004790:Enzyme Induction; D014644:Genetic Variation; D005838:Genotype; D005978:Glutathione / Q000378:metabolism; D006147:Guanine; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D018836:Inflammation Mediators / Q000378:metabolism; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013941:Thymine; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018836:Inflammation Mediators; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D006147:Guanine; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D005978:Glutathione; D013941:Thymine