QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.070789v1 311/3/1023    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marchesi, M. Articles by Lucchesi, B. R. Search for Related Content PubMed PubMed Citation Articles by Marchesi, M. Articles by Lucchesi, B. R.

CARDIOVASCULAR

Apolipoprotein A-I_Milano and 1-Palmitoyl-2-oleoyl Phosphatidylcholine Complex (ETC-216) Protects the in Vivo Rabbit Heart from Regional Ischemia-Reperfusion Injury

Department of Pharmacological Sciences, University of Milan, Milan, Italy (M.M.); Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (E.A.B., T.D., B.R.L.); and Department of Pharmacology, Esperion Therapeutics, Inc., a Division of Pfizer Global Research and Development, Ann Arbor, Michigan (C.L.B.)

Ex vivo studies demonstrated that a synthetic high-density lipoprotein (HDL) comprised of a complex of recombinant apolipoprotein A-I_Milano and 1-palmitoyl-2-oleoyl phosphatidylcholine protects the isolated rabbit heart from reperfusion injury. Therefore, we sought to determine whether a pharmaceutical preparation of this complex, ETC-216, was cardioprotective in an in vivo model of left anterior descending artery (LAD) occlusion and reperfusion. Initially, ETC-216 (100 mg/kg) was tested in acute (one-treatment) and chronic (two-treatment) i.v. administrations. ETC-216-treated rabbits developed smaller infarcts expressed as percentage of area at risk (p < 0.01) compared with vehicle treatments. No differences were noted between chronic and acute administration. Therefore, ETC-216 (10, 3, or 1 mg/kg) or equivalent vehicle volumes were acutely infused. Compared with vehicle, ETC-216 reduced infarct size as a percentage of the area at risk at 10 (p < 0.0005) and 3 mg/kg (p < 0.05). No significant differences occurred at 1 mg/kg. To determine whether ETC-216 could protect the heart after initiation of ischemia, the synthetic HDL (10 mg/kg) was infused intravenously beginning 5 min before the end of 30 min of LAD occlusion. Infarct size as percentage of the area at risk was 31.6 ± 3.0 (ETC-216) versus 49.5 ± 2.5 (vehicle) (p < 0.001), and as percentage of left ventricle was 19.7 ± 1.6 (ETC-216) versus 34.1 ± 2.3 (vehicle) (p < 0.0005). Electron microscopy demonstrated that ETC-216 prevented irreversible cardiac damage as assessed by mitochondrial granulation and sarcomere contraction band formation. These findings suggest ETC-216 reduces reperfusion injury and may have utility for coronary artery revascularization procedures.

Address correspondence to: Dr. Benedict R. Lucchesi, Department of Pharmacology, University of Michigan Medical School, 1301C Medical Science Research Bldg. III, Ann Arbor, MI 48109-0632. E-mail: benluc{at}umich.edu

This article has been cited by other articles:

				M. Gomaraschi, L. Calabresi, G. Rossoni, S. Iametti, G. Franceschini, J. A. Stonik, and A. T. Remaley Anti-Inflammatory and Cardioprotective Activities of Synthetic High-Density Lipoprotein Containing Apolipoprotein A-I Mimetic Peptides J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 776 - 783. [Abstract] [Full Text] [PDF]

				G. Florvall, S. Basu, and A. Larsson Apolipoprotein A1 Is a Stronger Prognostic Marker Than Are HDL and LDL Cholesterol for Cardiovascular Disease and Mortality in Elderly Men J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2006; 61(12): 1262 - 1266. [Abstract] [Full Text] [PDF]

				G. Theilmeier, C. Schmidt, J. Herrmann, P. Keul, M. Schafers, I. Herrgott, J. Mersmann, J. Larmann, S. Hermann, J. Stypmann, et al. High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P3 Lysophospholipid Receptor Circulation, September 26, 2006; 114(13): 1403 - 1409. [Abstract] [Full Text] [PDF]