title: Apolipoprotein A-IMilano and 1-palmitoyl-2-oleoyl phosphatidylcholine complex (ETC-216) protects the in vivo rabbit heart from regional ischemia-reperfusion injury.
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.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, 1301C Medical Science Research Bldg. III, Ann Arbor, MI 48109-0632, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Marchesi
authors.forename: Erin A
authors.initials: EA
authors.lastname: Booth
authors.forename: Treasa
authors.initials: T
authors.lastname: Davis
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bisgaier
authors.forename: Benedict R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008854:Microscopy, Electron; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010713:Phosphatidylcholines / Q000627:therapeutic use*; D011817:Rabbits; D013997:Time Factors
chemical_list: D016632:Apolipoprotein A-I; C474616:ETC216; D008074:Lipoproteins; D010713:Phosphatidylcholines; C080631:apolipoprotein A-I Milano; D002784:Cholesterol