Increased superoxide anion formation in endothelial cells during hyperglycemia: an adaptive response or initial step of vascular dysfunction?

In diabetes mellitus, the risk for cardiovascular complications and development of atherosclerosis is increased compared with healthy individuals. Recently evidence was provided that increased production of superoxide anions occurs in endothelial cells during hyperglycemia. In order to evaluate the potential impact of the enhanced formation of this oxygen radical for vascular cell dysfunction and its role in tissue adaptation, it is essential to assess the effect of superoxide anions on endothelial cell function. Here, we present new data and review our previous work on the effects of superoxide anions on endothelial vascular function, such as intracellular Ca2+ signal cascade, formation and bioactivity of nitric oxide. Based on the presented data we discuss superoxide anion production as a two faced phenomenon. In lower concentrations, superoxide anions are mediators of an endothelium adaptation to ensure endothelial vasomotion control. However, in higher concentrations superoxide anions disrupt endothelial-smooth muscle crosstalk resulting in vessel wall dysfunction and vascular wall dysfunction.

[1]  W. Graier,et al.  Cytochrome P450 mono‐oxygenase‐regulated signalling of Ca2+ entry in human and bovine endothelial cells. , 1995, The Journal of physiology.

[2]  O. Hornykiewicz,et al.  The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment. , 1986, European journal of pharmacology.

[3]  R. Tsien,et al.  A new generation of Ca2+ indicators with greatly improved fluorescence properties. , 1985, The Journal of biological chemistry.

[4]  M. Auclair,et al.  Glucose‐enriched medium enhances cell‐mediated low density lipoprotein peroxidation , 1995, FEBS letters.

[5]  W. Graier,et al.  Effects of superoxide anions on endothelial Ca2+ signaling pathways. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[6]  A. Hermetter,et al.  Vascular effects of L-arginine: anything beyond a substrate for the NO-synthase? , 1997, Biochemical and biophysical research communications.

[7]  R. Greenwald,et al.  Oxy radicals and their scavenger systems : proceedings of the Third International Conference on Superoxide and Superoxide Dismutase, Ellenville, New York, October 3-8, 1982 , 1983 .

[8]  T. Wascher,et al.  Time course of endothelial dysfunction in diabetes mellitus. , 1994, Circulation.

[9]  Mogensen Ce.  Glomerular Filtration Rate and Renal Plasma Flow in Short-term and Long-term Juvenile Diabetes Mellitus , 1971 .

[10]  T. Wascher,et al.  Antioxidants prevent high-D-glucose-enhanced endothelial Ca2+/cGMP response by scavenging superoxide anions. , 1997, European journal of pharmacology.

[11]  J. Nyengaard,et al.  Hyperglycemic Pseudohypoxia and Diabetic Complications , 1993, Diabetes.

[12]  T. Wascher,et al.  Exposure To Elevated D-Glucose Concentrations Modulates Vascular Endothelial Cell Vasodilatory Response , 1993, Diabetes.

[13]  W. Graier,et al.  High D-Glucose–Induced Changes in Endothelial Ca2+/EDRF Signaling are Due to Generation of Superoxide Anions , 1996, Diabetes.

[14]  D. Slaaf,et al.  Skin blood cell flux in insulin‐dependent diabetic subjects in relation to retinopathy or incipient nephropathy , 1992, European journal of clinical investigation.

[15]  A. Azzi,et al.  High rates of extracellular superoxide generation by cultured human fibroblasts: involvement of a lipid-metabolizing enzyme. , 1996, The Biochemical journal.

[16]  R. Cohen,et al.  DISFUNCTION OF VASCULAR ENDOTHELIUM IN DIABETES MELLITUS , 1993 .

[17]  T. Wascher,et al.  Role of superoxide anions in changes of endothelial vasoactive response during acute hyperglycemia. , 1997, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[18]  R. Cohen,et al.  15‐Hydroxyeicosatetraenoic Acid and Diabetic Endothelial Dysfunction in Rabbit Aorta , 1995, Journal of cardiovascular pharmacology.

[19]  R. Cohen,et al.  Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TxA2. , 1989, The American journal of physiology.

[20]  S. J. Elliott,et al.  Oxidant stress inhibits the store-dependent Ca(2+)-influx pathway of vascular endothelial cells. , 1993, The Biochemical journal.

[21]  K. Kamata,et al.  Impairment of endothelium‐dependent relaxation and changes in levels of cyclic GMP in aorta from streptozotocin‐induced diabetic rats , 1989, British journal of pharmacology.

[22]  G. Krejs,et al.  Intracellular Mechanisms Involved in D-Glucose–Mediated Amplification of Agonist-Induced Ca2+ Response and EDRF Formation in Vascular Endothelial Cells , 1994, Diabetes.

[23]  R. Cohen,et al.  Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. , 1990, The Journal of clinical investigation.

[24]  P. Gallop,et al.  An NADPH oxidase superoxide-generating system in the rabbit aorta. , 1995, The American journal of physiology.

[25]  R. Cohen,et al.  Free radicals mediate endothelial cell dysfunction caused by elevated glucose. , 1992, The American journal of physiology.

[26]  W. Graier,et al.  Ca2+ Regulation and Endothelial Vascular Function , 1994 .

[27]  Y. Hattori,et al.  Attenuation of endothelium-dependent relaxation in aorta from diabetic rats. , 1986, European journal of pharmacology.

[28]  A. Thomson,et al.  Endothelium-Dependent Relaxation in Aorta of BB Rat , 1987, Diabetes.

[29]  P. Cerutti,et al.  High Glucose Induces Antioxidant Enzymes in Human Endothelial Cells in Culture: Evidence Linking Hyperglycemia and Oxidative Stress , 1996, Diabetes.

[30]  H. Granger,et al.  Calcium entry, mobilization, and extrusion in postcapillary venular endothelium exposed to bradykinin. , 1993, The American journal of physiology.