Abstract
Ex vivo studies demonstrated that a synthetic high-density lipoprotein (HDL) comprised of a complex of recombinant apolipoprotein A-IMilano 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.
Footnotes
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This study was supported by a Research Agreement between Esperion Therapeutics, Inc. and the Cardiovascular Pharmacology Research Fund, University of Michigan Medical School. This work, in part, was in fulfillment of the doctoral thesis requirements of M.M. for the University of Milan, Milan, Italy (guide Professor Cesare R. Sirtori).
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doi:10.1124/jpet.104.070789.
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ABBREVIATIONS: HDL-C, high-density lipoprotein cholesterol; HDL, high-density lipoprotein; ApoA-IMilano, apolipoprotein A-IMilano; POPC, 1-palmitoyl-2-oleoyl phosphatidylcholine; ETC-216, ApoA-IMilano complexed with 1-palmitoyl-2-oleoyl phosphatidylcholine; LAD, left anterior descending artery; TTC, triphenyltetrazolium chloride; AAR, area at risk; LV, left ventricle; VLDL, very low-density lipoprotein; LDL, low-density lipoprotein; RPP, rate-pressure product.
- Received April 30, 2004.
- Accepted September 16, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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