Santhanam Anantha Vijay R, d'Uscio Livius V, Katusic Zvonimir S
Departments of Anesthesiology, and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
J Neurochem. 2014 Nov;131(4):521-9. doi: 10.1111/jnc.12824. Epub 2014 Aug 6.
This study was designed to determine whether treatment with erythropoietin (EPO) could protect cerebral microvasculature against the pathological consequences of endothelial nitric oxide (NO) synthase uncoupling. Wild-type and GTP cyclohydrolase I (GTPCH-I)-deficient hph1 mice were administered EPO (1000 U/kg/day, s.c., 3 days). Cerebral microvessels of hph1 mice demonstrated reduced tetrahydrobiopterin (BH4) bioavailability, increased production of superoxide anions and impaired endothelial NO signaling. Treatment of hph1 mice with EPO attenuated the levels of 7,8-dihydrobiopterin, the oxidized product of BH4, and significantly increased the ratio of BH4 to 7,8-dihydrobiopterin. Moreover, EPO decreased the levels of superoxide anions and increased NO bioavailability in cerebral microvessels of hph1 mice. Attenuated oxidation of BH4 and inhibition of endothelial NO synthase uncoupling were explained by the increased expression of antioxidant proteins, manganese superoxide dismutase, and catalase. The protective effects of EPO observed in cerebral microvessels of hph1 mice were also observed in GTPCH-I siRNA-treated human brain microvascular endothelial cells exposed to EPO (1 U/mL or 10 U/mL; 3 days). Our results suggest that EPO might protect the neurovascular unit against oxidative stress by restoring bioavailability of BH4 and endothelial NO in the cerebral microvascular endothelium. We demonstrate that treatment with erythropoietin (EPO) could protect cerebral microvasculature against the pathological consequences of endothelial nitric oxide (NO) synthase uncoupling. Our results suggest that EPO might protect the neurovascular unit against oxidative stress by restoring bioavailability of tetrahydrobiopterin (BH4) and endothelial nitric oxide.
本研究旨在确定促红细胞生成素（EPO）治疗是否能保护脑微血管免受内皮型一氧化氮（NO）合酶解偶联的病理后果影响。对野生型和GTP环水解酶I（GTPCH-I）缺陷的hph1小鼠给予EPO（1000 U/kg/天，皮下注射，共3天）。hph1小鼠的脑微血管显示四氢生物蝶呤（BH4）生物利用度降低、超氧阴离子生成增加以及内皮型NO信号传导受损。用EPO治疗hph1小鼠可降低BH4的氧化产物7,8-二氢生物蝶呤的水平，并显著提高BH4与7,8-二氢生物蝶呤的比值。此外，EPO降低了hph1小鼠脑微血管中超氧阴离子的水平并增加了NO的生物利用度。BH4氧化的减弱和内皮型NO合酶解偶联的抑制可通过抗氧化蛋白、锰超氧化物歧化酶和过氧化氢酶表达的增加来解释。在接受EPO（1 U/mL或10 U/mL；3天）处理的GTPCH-I siRNA转染的人脑微血管内皮细胞中也观察到了EPO在hph1小鼠脑微血管中所观察到的保护作用。我们的结果表明，EPO可能通过恢复脑微血管内皮细胞中BH4和内皮型NO的生物利用度来保护神经血管单元免受氧化应激。我们证明，促红细胞生成素（EPO）治疗可保护脑微血管免受内皮型一氧化氮（NO）合酶解偶联的病理后果影响。我们的结果表明，EPO可能通过恢复四氢生物蝶呤（BH4）和内皮型一氧化氮的生物利用度来保护神经血管单元免受氧化应激。
