Erythropoietin attenuated vascular dysfunction and inflammation by inhibiting NADPH oxidase-derived superoxide production in nitric oxide synthase-inhibited hypertensive rat aorta.
Erythropoietin (EPO), used clinically for renal anemia, reportedly exerts beneficial pleiotropic effects in various tissues. Recent studies suggest that nitric oxide (NO) plays an important role in EPO-induced tissue protection. The present study investigated whether recombinant human EPO (rHuEPO) exhibits vasoprotective effects even in the NO synthase-inhibited state. Rats that received a NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), in drinking water (0.7 mg/ml) were treated with rHuEPO (75 U/kg, s.c.) three times a week for 2 weeks. The administration of rHuEPO to L-NAME-treated rats had no effect on hematocrit values or increased blood pressure. Vasodilation in response to acetylcholine in the aortic ring was impaired in the L-NAME-treated rats, and improved by rHuEPO. Immunohistochemical staining revealed that infiltration by macrophages and expression of osteopontin were enhanced in the L-NAME-treated rat aorta, and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Activation of Akt signaling was evident in rHuEPO-treated rats as the increased expression of phosphorylated Akt. rHuEPO enhanced the expression of antioxidant enzymes such as Cu/Zn-superoxide dismutase and heme oxygenase-1 in the aorta. In addition, rHuEPO reduced NADPH oxidase-dependent superoxide production and enhanced the expression of suppressor of cytokine signaling-1(SOCS-1) in the L-NAME-treated rat aorta. These results suggest that a low dose of rHuEPO results in the normalization of endothelial function and vascular inflammation beyond hematopoiesis even in a pharmacologically NO synthase-inhibited state. These effects might be due to the antioxidant properties of rHuEPO. SOCS-1 overexpression would play an important role in suppressing NADPH oxidase activation.
Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan. toba@mb.kyoto-phu.ac.jp
Hiroe
H
Toba
Yushi
Y
Kojima
Jiahong
J
Wang
Kazuki
K
Noda
Wei
W
Tian
Miyuki
M
Kobara
Tetsuo
T
Nakata
D000109:Acetylcholine / Q000494:pharmacology; D063194:Adventitia / Q000187:drug effects / Q000276:immunology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006400:Hematocrit; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009599:Nitroprusside / Q000494:pharmacology; D053495:Osteopontin / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
D010750:Phosphoproteins; C491589:Socs1 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053495:Osteopontin; D013481:Superoxides; D004921:Erythropoietin; D009599:Nitroprusside; D019001:Nitric Oxide Synthase; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester