Abstract
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 μg/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.
Footnotes
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This study was supported by National Institutes of Health Grants DK068134, HL55601, and HL34300 (to N.G.A.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.119479.
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ABBREVIATIONS: apoA-I, apolipoprotein A-I; D-4F, apolipoprotein A1 mimetic peptide; EC, endothelial cell; CD31, endothelial cell marker; TM, thrombomodulin; EPC, endothelial progenitor cell; HO, heme oxygenase; eNOS, endothelial nitric-oxide synthase; STZ, streptozotocin; LDL, low-density lipoprotein; ELISA, enzyme-linked immunosorbent assay; CEC, circulating endothelial cell; FACS, fluorescence-activated cell sorting.
- Received January 5, 2007.
- Accepted May 2, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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