Long-term treatment with the apoliprotein A1 mimetic peptide increases antioxidants and vascular repair in type I diabetic rats
Long-term treatment with the apoliprotein A1 mimetic peptide increases antioxidants and vascular repair in type I diabetic rats
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DOI：
10.1124/jpet.107.119479
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
Abraham, Nader G.
中科院分区：
文献类型：
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作者：
Peterson, Stephen J.;Husney, Daniel;Abraham, Nader G.
载脂蛋白A1模拟肽(D-4F)是由D-氨基酸合成的，能增强高密度脂蛋白在动脉粥样硬化性疾病中保护低密度脂蛋白(LDL)免受氧化的能力。采用I型糖尿病大鼠模型，研究长期使用D-4F是否会导致HO-1、内皮细胞标志物CD31(+)和血栓调节蛋白(TM)的表达上调，并增加内皮祖细胞(EPC)的数量。用链脲佐菌素(STZ)复制SD大鼠糖尿病模型，给D-4F或赋形剂灌胃。每日注射，连续6周(100微克/100克体重)。测定肝脏、肾脏、心脏和主动脉的HO活性。D-4F治疗6周后，心脏和主动脉HO活性分别显著增加29%和31%(p<；0.05和p<；0.49)。长期D-4F治疗后，TM和CD31(+)的表达也显著增加。给予D-4F可增加抗氧化能力，表现为氧化蛋白和氧化低密度脂蛋白的减少，增强EPC功能和/或修复，表现为EPC内皮型一氧化氮合酶(ENOS)的增加，并防止血管TM和CD31+丢失。总之，HO-1和eNOS是D-4F的相关靶点，可能有助于D-4F介导的TM和CD31(+)的增加，以及抗氧化和抗炎特性，并在这一1型糖尿病动物模型中提供强大的血管保护。
Apolipoprotein A1 mimetic peptide (D-4F), synthesized from D-amino acid, enhances the ability of high-density lipoprotein to protect low-density lipoprotein (LDL) against oxidation in atherosclerotic disease. Using a rat model of type I diabetes, we investigated whether chronic use of D-4F would lead to up-regulation of heme oxygenase (HO)-1, endothelial cell marker (CD31(+)), and thrombomodulin (TM) expression and increase the number of endothelial progenitor cells (EPCs). Sprague-Dawley rats were rendered diabetic with streptozotocin (STZ) and either D-4F or vehicle was administered, by i.p. injection, daily for 6 weeks (100 mu g/100 g b.wt.). HO activity was measured in liver, kidney, heart, and aorta. After 6 weeks of D-4F treatment, HO activity significantly increased in the heart and aorta by 29 and 31% (p < 0.05 and p < 0.49), respectively. Long-term D-4F treatment also caused a significant increase in TM and CD31(+) expression. D-4F administration increased antioxidant capacity, as reflected by the decrease in oxidized protein and oxidized LDL, and enhanced EPC function and/or repair, as evidenced by the increase in EPC endothelial nitric-oxide synthase (eNOS) and prevention of vascular TM and CD31+ loss. In conclusion, HO-1 and eNOS are relevant targets for D-4F and may contribute to the D-4F-mediated increase in TM and CD31(+), the antioxidant and anti-inflammatory properties, and confers robust vascular protection in this animal model of type 1 diabetes.