Modulation of antioxidant enzyme expression and function by estrogen.
Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzyme activity and expression. The vasoprotective effects of estrogens may be related to antioxidative properties. Therefore, effects of 17beta-estradiol on production of reactive oxygen species and radical scavenging enzymes were investigated. 17beta-estradiol diminished angiotensin II-induced free radical production in vascular smooth muscle cells (DCF fluorescence laser microscopy). 17beta-estradiol time- and concentration-dependently upregulated manganese (MnSOD) and extracellular superoxide dismutase (ecSOD) expression (Northern and Western blotting) and enzyme activity (photometric assay). Nuclear run-on assays demonstrated that 17beta-estradiol increases MnSOD and ecSOD transcription rate. Half-life of MnSOD mRNA was not influenced, whereas ecSOD mRNA was stabilized by estrogen. Copper-zinc SOD, glutathione-peroxidase, and catalase were not affected by estrogen. Estrogen deficiency in ovariectomized mice induced a downregulation of ecSOD and MnSOD expression, which was associated with increased production of vascular free radicals and prevented by estrogen replacement or treatment with PEG-SOD. In humans, increased estrogen levels led to enhanced ecSOD and MnSOD expression in circulating monocytes. Estrogen acts antioxidative at least to some extent via stimulation of MnSOD and ecSOD expression and activity, which may contribute to its vasoprotective effects.
Strehlow
Kerstin
K
Medizinische Klinik und Poliklinik, Innere Medizin III, Universitätskliniken des Saarlandes, Homburg/Saar, Germany.
Rotter
Simone
S
Wassmann
Sven
S
Adam
Oliver
O
Grohé
Christian
C
Laufs
Kerstin
K
Böhm
Michael
M
Nickenig
Georg
G
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D016166:Free Radical Scavengers / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010052:Ovariectomy; D011092:Polyethylene Glycols / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
D000975:Antioxidants; D016166:Free Radical Scavengers; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D000804:Angiotensin II; D011092:Polyethylene Glycols; D004958:Estradiol; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase