title: Endothelial dysfunction, macrophage infiltration and NADPH oxidase-dependent superoxide production were attenuated by erythropoietin in streptozotocin-induced diabetic rat aorta.
abstract: Erythropoietin (EPO) has been used for the management of renal anemia. Recent studies suggest the pleiotropic properties of EPO in various tissues such as brain, kidney and vasculature. Diabetes mellitus is a major risk for development of vascular impairment. The aim of the present study was to investigate the hypothesis that EPO would be beneficial in inhibiting diabetic macroangiopathy. Recombinant human EPO (rHuEPO; 150 U/kg, 3 times/week, s.c.) was administered to streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, i.v.) significantly increased macrophage infiltration and adhesion molecules, monocyte chemoattractant protein-1 and osteopontin mRNA levels in the aorta. These inflammatory changes were suppressed by rHuEPO. Vasodilation in response to acetylcholine in the aortic ring was impaired in the diabetic rats, and improved by rHuEPO. rHuEPO inhibited the aortic expression of mRNA for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the NADPH oxidase-dependent superoxide production and the increase in plasma malondialdehyde concentration in diabetic rats. rHuEPO also decreased the level of the receptor for advanced glycation end products in the aorta. We also found an increased expression of phospho-Akt and endothelial nitric oxide synthase and plasma NOx level in the rHuEPO-treated group. On the other hand, rHuEPO did not affect blood glucose levels, hemoglobin A(1c), blood pressure or hematocrit in diabetic rats. These results indicate that rHuEPO exerts pleiotropic antioxidant and anti-inflammatory properties in diabetic rat aorta.
authors.affiliation: Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Wang
authors.forename: Hiroe
authors.initials: H
authors.lastname: Toba
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Morita
authors.forename: Kohei
authors.initials: K
authors.lastname: Nakashima
authors.forename: Kazuki
authors.initials: K
authors.lastname: Noda
authors.forename: Wei
authors.initials: W
authors.lastname: Tian
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kobara
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nakata
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D018932:Chemokine CCL2 / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004921:Erythropoietin / Q000494:pharmacology*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D019255:NADPH Oxidases / Q000378:metabolism; D009589:Nitrogen Oxides / Q000097:blood; D053495:Osteopontin / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001786:Blood Glucose; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D006454:Hemoglobins; D009589:Nitrogen Oxides; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C506897:Spp1 protein, rat; D019010:Vascular Cell Adhesion Molecule-1; D053495:Osteopontin; D013481:Superoxides; D004921:Erythropoietin; D018799:Intercellular Adhesion Molecule-1; D008315:Malondialdehyde; D019255:NADPH Oxidases