Anti-inflammatory and cardioprotective activities of synthetic high-density lipoprotein containing apolipoprotein A-I mimetic peptides.
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 alpha-helical content. Pretreatment of endothelial cells with either peptide sHDL reduced tumor necrosis factor alpha-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 alpha (TNFalpha) 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.
National Institutes of Health, 10 Center Dr., Bldg. 10/Rm. 2C-433, Bethesda, MD 20892, USA.
Monica
M
Gomaraschi
Laura
L
Calabresi
Giuseppe
G
Rossoni
Stefania
S
Iametti
Guido
G
Franceschini
John A
JA
Stonik
Alan T
AT
Remaley
D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D016632:Apolipoprotein A-I / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D008075:Lipoproteins, HDL / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D002316:Cardiotonic Agents; D008075:Lipoproteins, HDL; D010455:Peptides; D019010:Vascular Cell Adhesion Molecule-1