D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes
D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes
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DOI：
10.1161/circulationaha.104.517102
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发表时间：
2005-06-14
期刊：
影响因子：
37.8
通讯作者：
Abraham, NG
中科院分区：
文献类型：
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作者：
Kruger, AL;Peterson, S;Abraham, NG
背景-载脂蛋白A1模拟肽，由d -氨基酸（D-4F）合成，增强了动脉粥样硬化动物HDL保护LDL抗氧化的能力。方法和结果-我们研究了D-4F在糖尿病模型中提供抗氧化作用的机制。Sprague-Dawley大鼠给药链脲佐菌素后发生糖尿病。我们检测了每日D-4F （100 μ g/100 g体重，腹腔注射）对糖尿病大鼠超氧化物（O-2）、细胞外超氧化物歧化酶（EC-SOD）、血管血红素加氧酶（HO-1和HO-2）水平和循环内皮细胞的影响。在D-4F的作用下，HO-1的数量和活性均有所增加。与对照组（38.1 +/- 8 × 10(3) cpm/10 mg蛋白）相比，糖尿病大鼠的O-2（-）水平升高（74.8 +/- 8 × 10(3) cpm/10 mg蛋白）；P < 0.01)。D-4F使O-2（-）水平降至13.23 +/- 1 × 10(3)（与未治疗糖尿病患者相比P < 0.05）。糖尿病患者循环内皮细胞的平均数量（50 +/- 6个细胞/mL）高于对照组（5 +/- 1个细胞/mL），而D-4F治疗的糖尿病患者循环内皮细胞的平均数量（20 +/- 3个细胞/mL， P < 0.005）显著降低。D-4F还能减少糖尿病大鼠内皮细胞的断裂。给药D-4F（85.0 +/- 2.0%松弛）可防止糖尿病大鼠血管松弛受损。Western blot分析显示糖尿病大鼠EC-SOD降低，而D-4F使EC-SOD水平恢复。结论-我们得出结论，糖尿病大鼠循环内皮细胞脱落、超氧阴离子和血管收缩的增加可以通过给予D-4F来预防，这与2种抗氧化蛋白HO-1和EC-SOD的增加有关。
Background - Apolipoprotein A1 mimetic peptide, synthesized from D-amino acid (D-4F), enhances the ability of HDL to protect LDL against oxidation in atherosclerotic animals.Methods and Results - We investigated the mechanisms by which D-4F provides antioxidant effects in a diabetic model. Sprague-Dawley rats developed diabetes with administration of streptozotocin (STZ). We examined the effects of daily D-4F (100 mu g/100 g of body weight, intraperitoneal injection) on superoxide (O-2(-)), extracellular superoxide dismutase (EC-SOD), vascular heme oxygenase (HO-1 and HO-2) levels, and circulating endothelial cells in diabetic rats. In response to D-4F, both the quantity and activity of HO-1 were increased. O-2(-) levels were elevated in diabetic rats (74.8 +/- 8 x 10(3) cpm/10 mg protein) compared with controls (38.1 +/- 8 x 10(3) cpm/10 mg protein; P < 0.01). D-4F decreased O-2(-) levels to 13.23 +/- 1 x 10(3) ( P < 0.05 compared with untreated diabetics). The average number of circulating endothelial cells was higher in diabetics (50 +/- 6 cells/ mL) than in controls (5 +/- 1 cells/mL) and was significantly decreased in diabetics treated with D-4F (20 +/- 3 cells/ mL; P < 0.005). D-4F also decreased endothelial cell fragmentation in diabetic rats. The impaired relaxation typical of blood vessels in diabetic rats was prevented by administration of D-4F (85.0 +/- 2.0% relaxation). Western blot analysis showed decreased EC-SOD in the diabetic rats, whereas D-4F restored the EC-SOD level.Conclusions - We conclude that an increase in circulating endothelial cell sloughing, superoxide anion, and vasoconstriction in diabetic rats can be prevented by administration of D-4F, which is associated with an increase in 2 antioxidant proteins, HO-1 and EC-SOD.