Modulation of Antioxidant Enzyme Expression and Function by Estrogen

&NA; 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 17&bgr;‐estradiol on production of reactive oxygen species and radical scavenging enzymes were investigated. 17&bgr;‐estradiol diminished angiotensin II‐induced free radical production in vascular smooth muscle cells (DCF fluorescence laser microscopy). 17&bgr;‐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 17&bgr;‐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. (Circ Res. 2003;93:170‐177.)

[1]  Charles Kooperberg,et al.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. , 2002, JAMA.

[2]  Deborah Grady,et al.  Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). , 2002, JAMA.

[3]  R. Karas,et al.  The protective effects of estrogen on the cardiovascular system. , 2002, The New England journal of medicine.

[4]  R. Behl,et al.  FSH induced stimulation of catalase activity in goat granulosa cells in vitro. , 2002, Animal reproduction science.

[5]  H. Brown-Borg,et al.  Effects of Growth Hormone and Insulin-Like Growth Factor-1 on Hepatocyte Antioxidative Enzymes , 2002, Experimental biology and medicine.

[6]  M. Boegehold,et al.  Effect of a High Salt Diet on Microvascular Antioxidant Enzymes , 2002, Journal of Vascular Research.

[7]  M. Hung,et al.  Akt activation by estrogen in estrogen receptor-negative breast cancer cells. , 2001, Cancer research.

[8]  Y. Katagiri,et al.  Heparin-stimulated expression of extracellular-superoxide dismutase in human fibroblasts. , 2001, Atherosclerosis.

[9]  W. Aird,et al.  Vascular endothelial growth factor induces manganese‐superoxide dismutase expression in endothelial cells by a Racl‐regulated NADPH oxidase‐dependent mechanism , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  J. Cauley,et al.  Effect of Estrogen plus Progestin on Risk for Biliary Tract Surgery in Postmenopausal Women with Coronary Artery Disease: The Heart and Estrogen/progestin Replacement Study , 2001, Annals of Internal Medicine.

[11]  M. Hecker,et al.  17β‐Estradiol inhibition of NADPH oxidase expression in human endothelial cells , 2001 .

[12]  V. Muzykantov Targeting of superoxide dismutase and catalase to vascular endothelium. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[13]  H. Drexler,et al.  Comparative Effect of ACE Inhibition and Angiotensin II Type 1 Receptor Antagonism on Bioavailability of Nitric Oxide in Patients With Coronary Artery Disease: Role of Superoxide Dismutase , 2001, Circulation.

[14]  G. Nickenig,et al.  Endothelial Dysfunction and Oxidative Stress During Estrogen Deficiency in Spontaneously Hypertensive Rats , 2001, Circulation.

[15]  G. Nickenig,et al.  Differential Effects of Estrogen and Progesterone on AT1 Receptor Gene Expression in Vascular Smooth Muscle Cells , 2000, Circulation.

[16]  K. Irani Oxidant signaling in vascular cell growth, death, and survival : a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. , 2000, Circulation research.

[17]  H. Jo,et al.  Cell signaling by reactive nitrogen and oxygen species in atherosclerosis. , 2000, Free radical biology & medicine.

[18]  G. Kojda,et al.  Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. , 2000, The Journal of clinical investigation.

[19]  H. Drexler,et al.  Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. , 2000, Circulation.

[20]  J. Pfeilschifter,et al.  Identification of copper/zinc superoxide dismutase as a nitric oxide-regulated gene in human (HaCaT) keratinocytes: implications for keratinocyte proliferation. , 2000, The Biochemical journal.

[21]  F. Sánchez-Jiménez,et al.  Role of reactive oxygen species in apoptosis: implications for cancer therapy. , 2000, The international journal of biochemistry & cell biology.

[22]  R. Nagai,et al.  Inducible expression of manganese superoxide dismutase by phorbol 12-myristate 13-acetate is mediated by Sp1 in endothelial cells. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[23]  J. Matés,et al.  Antioxidant enzymes and human diseases. , 1999, Clinical biochemistry.

[24]  L. Ji,et al.  Superoxide dismutase gene expression in skeletal muscle: fiber-specific adaptation to endurance training. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[25]  B. Berk Redox Signals that Regulate the Vascular Response to Injury , 1999, Thrombosis and Haemostasis.

[26]  D. Harrison,et al.  Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. , 1999, Circulation research.

[27]  R. Busse,et al.  Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation , 1999, Nature.

[28]  C. Thiemermann,et al.  Identification of copper/zinc superoxide dismutase as a novel nitric oxide‐regulated gene in rat glomerular mesangial cells and kidneys of endotoxemic rats , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  G. Gibori,et al.  Differential regulation of copper-zinc superoxide dismutase and manganese superoxide dismutase in the rat corpus luteum: induction of manganese superoxide dismutase messenger ribonucleic acid by inflammatory cytokines. , 1998, Biology of reproduction.

[30]  S. Rosenkranz,et al.  Estrogen modulates AT1 receptor gene expression in vitro and in vivo. , 1998, Circulation.

[31]  D. Harrison,et al.  Vascular expression of extracellular superoxide dismutase in atherosclerosis. , 1998, The Journal of clinical investigation.

[32]  G. Garcı́a-Cardeña,et al.  17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. , 1997, Circulation research.

[33]  J. Crapo,et al.  Extracellular superoxide dismutase is upregulated with inducible nitric oxide synthase after NF-κB activation. , 1997, American journal of physiology. Lung cellular and molecular physiology.

[34]  D. Harrison Endothelial Function and Oxidant Stress , 1997, Clinical cardiology.

[35]  C. Rosenfeld,et al.  Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium. , 1997, The American journal of physiology.

[36]  R. Vogel Coronary risk factors, endothelial function, and atherosclerosis: A review , 1997, Clinical cardiology.

[37]  T. Oury,et al.  Extracellular superoxide dismutase: a regulator of nitric oxide bioavailability. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[38]  A. Nègre-Salvayre,et al.  Ethinylestradiol does not enhance the expression of nitric oxide synthase in bovine endothelial cells but increases the release of bioactive nitric oxide by inhibiting superoxide anion production. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[39]  N. Wenger,et al.  Cardiovascular health and disease in women. , 1993, The New England journal of medicine.

[40]  R. Ross The pathogenesis of atherosclerosis: a perspective for the 1990s , 1993, Nature.

[41]  S. Marklund Regulation by cytokines of extracellular superoxide dismutase and other superoxide dismutase isoenzymes in fibroblasts. , 1992, The Journal of biological chemistry.

[42]  M. Hong,et al.  Effects of estrogen replacement therapy on serum lipid values and angiographically defined coronary artery disease in postmenopausal women. , 1992, The American journal of cardiology.

[43]  P. Poole‐Wilson,et al.  Endothelium‐independent relaxation of rabbit coronary artery by 17β‐oestradiol in vitro , 1991, British journal of pharmacology.

[44]  L. Oberley,et al.  An assay for superoxide dismutase activity in mammalian tissue homogenates. , 1989, Analytical biochemistry.

[45]  N. Sugino,et al.  Differential regulation of copper-zinc superoxide dismutase and manganese superoxide dismutase by progesterone withdrawal in human endometrial stromal cells. , 2002, Molecular human reproduction.

[46]  M. Dieudonné,et al.  Rapid nongenomic E2 effects on p42/p44 MAPK, activator protein-1, and cAMP response element binding protein in rat white adipocytes. , 2002, Endocrinology.

[47]  J. Keaney,et al.  Redox control of vascular nitric oxide bioavailability. , 2000, Antioxidants & redox signaling.

[48]  H. Jo,et al.  Nitric oxide, free radicals and cell signalling in cardiovascular disease. , 1997, Biochemical Society transactions.

[49]  A. Whittemore,et al.  Menopause and the risk of coronary heart disease in women. , 1987, The New England journal of medicine.