Abstract
Apolipoprotein A-I (apoA-I) mimetic peptides may represent an alternative to apoA-I for large-scale production of synthetic high-density lipoproteins (sHDL) as a therapeutic agent. In this study, the cardioprotective activity of sHDL made with either L37pA peptide or its d-stereoisomer, D37pA, was compared to sHDL made with apoA-I. The peptides were reconstituted with palmitoyl-oleoyl-phosphatidylcholine, which yielded sHDL particles comparable to apoA-I sHDL in diameter, molecular weight, and α-helical content. Pretreatment of endothelial cells with either peptide sHDL reduced tumor necrosis factor α-stimulated vascular cell adhesion molecule-1 expression to the same extent as apoA-I sHDL. In an isolated rat heart model of ischemia/reperfusion (I/R) injury, L37pA and D37pA sHDL significantly reduced postischemic cardiac contractile dysfunction compared to the saline control, as indicated by a 49.7 ± 6.4% (L37pA; P < 0.001) and 53.0 ± 9.1% (D37pA; P < 0.001) increase of left ventricular-developed pressure (LVDP) after reperfusion and by a 45.4 ± 3.4% (L37pA; P < 0.001) and 49.6 ± 2.6% (D37pA; P < 0.001) decrease of creatine kinase (CK) release. These effects were similar to the 51.3 ± 3.0% (P < 0.001) increase of LVDP and 51.3 ± 3.0 (P < 0.001) reduction of CK release induced by apoA-I sHDL. Consistent with their cardioprotective effects, all three types of sHDL particles mediated an approximate 20% (P < 0.001) reduction of cardiac tumor necrosis factor α (TNFα) content and stimulated an approximate 35% (P < 0.05) increase in postischemic release of prostacyclin. In summary, L37pA and D37pA peptides can form sHDL particles that retain a similar level of protective activity as apoA-I sHDL on the endothelium and the heart; thus, apoA-I mimetic peptides may be useful therapeutic agents for the prevention of cardiac I/R injury.
Footnotes
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This work was supported by intramural research funds from NHLBI, National Institutes of Health (Bethesda, MD) (to A.T.R. and J.A.S.).
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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.107.129411.
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ABBREVIATIONS: HDL, high-density lipoprotein; sHDL, synthetic HDL; I/R, ischemia/reperfusion; apoA-I, apolipoprotein A-I; POPC, palmitoyl-oleoyl-phosphatidylcholine; CD, circular dichroism; LVDP, left ventricular-developed pressure; CPP, coronary perfusion pressure; HUVEC, human umbilical vein endothelial cells; VCAM, vascular cell adhesion molecule; ELISA, enzyme-linked immunosorbent assay; RT-PCR, reverse transcription-polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; K-H, Krebs-Henseleit; CK, creatine kinase; PGI2, prostacyclin; AUC, area under the curve; NF-κB, nuclear factor κB; S1P, sphingosine-1-phosphate.
- Received August 6, 2007.
- Accepted November 26, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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