Apolipoprotein A-I_Milanoand 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-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 Ͻ 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,

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P 3 Lysophospholipid Receptor

“…6,34 Exogenous HDL mimetics, such as reconstituted HDL particles, recombinant apolipoprotein A1, or apolipoprotein A1 Milano, have the advantage of rapid bioavailability and immediate effects 13 and have been shown to reduce ischemia/reperfusion injury in rabbits (ETC-216). 35 In this respect and on the basis of the present study, S1P analogues may also be considered as functional HDL mimetics, especially because structural S1P homologs such as FTY720, currently in phase III clinical trials for immunosuppression in kidney transplant patients, 36 potently generate NO via the same mechanism as S1P contained in the HDL particle. 37 Furthermore, the S1P content of HDL may not only be a target for intervention but also constitute a novel predictor of cardiovascular risk, because 54% of the total plasma S1P is contained in HDL.…”

Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo

“…Thus, selective HDL delipidation has potential as a therapy for atherosclerosis, and a Phase 1 pilot trial has been completed in patients with CHD. Potential therapeutic applications for selective HDL delipidation also include acute coronary syndrome, acute stroke (46), coronary ischemia-reperfusion injury (47,48), and in-stent stenosis (49).…”

The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties

“…The differences in lipid composition of various subclasses of HDL and how they relate to disease have been gaining attention in recent years (12)(13)(14). However, a single source of lipid is used for preparation of rHDL for most academic research and clinical development (2)(3)(4)(5)(15)(16)(17)(18). The fi rst lipid used to prepare rHDLs for human testing was soybean PC (soyPC), because this lipid was shown to be safe for parenteral nutrition products and is readily commercially available in infusion grade ( 18 ).…”

“…As a greater variety of infusion grade chemically defi ned lipids became commercially available, the PL composition used in the preparation of rHDL diversifi ed. A POPC was fi rst used in ETC-216 (rApoA-I-Milano), and then a mixture of 1,2-dipalmitoyl-sn -glycero-3-phosphocholine (DPPC) and SM was used for ETC-642, a peptide-based rHDL ( 17,19 ). Most recently, SM was used in CER-001, another newly developed rApoA-I-based rHDL ( 20 ).…”