Apolipoprotein A-IMilano/POPC complex attenuates post-ischemic ventricular dysfunction in the isolated rabbit heart

Marchesi, Marta; Booth, Erin A.; Rossoni, Giuseppe; García, Ricardo A.; Hill, Knut R.; Sirtori, Cesare R.; Bisgaier, Charles L.; Lucchesi, Benedict R.

doi:10.1016/j.atherosclerosis.2007.08.028

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Volume 197, Issue 2 , Pages 572-578, April 2008

Apolipoprotein A-I_Milano/POPC complex attenuates post-ischemic ventricular dysfunction in the isolated rabbit heart

Marta Marchesi
- Department of Pharmacological Sciences, University of Milan, Italy
- Corresponding author. Tel.: +39 02 50318328; fax: +39 02 50318284.
Erin A. Booth
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
Giuseppe Rossoni
- Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy
Ricardo A. García
- Esperion Therapeutics, Division of Pfizer Global Research and Development, Ann Arbor, MI, USA
Knut R. Hill
- Esperion Therapeutics, Division of Pfizer Global Research and Development, Ann Arbor, MI, USA
Cesare R. Sirtori
- Department of Pharmacological Sciences, University of Milan, Italy
Charles L. Bisgaier
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
- Esperion Therapeutics, Division of Pfizer Global Research and Development, Ann Arbor, MI, USA
Benedict R. Lucchesi
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

Received 17 April 2007; received in revised form 17 August 2007; accepted 20 August 2007. published online 18 October 2007.

Abstract

Irreversible myocardial injury is a potential consequence of coronary artery revascularization. Reperfusion leads to the production of oxidized products that can damage myocardium. High-density lipoproteins (HDL) are effective at removing oxidized lipids. We hypothesized that a synthetic HDL preparation, comprising recombinant apolipoprotein A-I_Milano (apoA-I_M) complexed with 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) (apoA-I_M/POPC) would protect the heart from reperfusion injury. The ex vivo model consisted of rabbit hearts perfused by the Langendorff method. Hearts were equilibrated with Krebs–Henseleit buffer (10min), pretreated with either apoA-I_M/POPC (0.45mg/mL) or vehicle (10min), subjected to global ischemia (30min) and reperfused for 60min. ApoA-I_M/POPC (n=7) prevented the left ventricular end-diastolic pressure elevation observed in the vehicle group (n=6) at the end of reperfusion (p<0.05). During reperfusion, coronary artery perfusion pressure increased in the controls (p<0.001), but not with apoA-I_M/POPC. ApoA-I_M/POPC reduced the release of creatine kinase at the end of the ischemic period (p<0.001). It also reduced cardiac left ventricle muscle lipid hydroperoxides by 46% (p<0.05). Direct comparison of the antioxidant potential indicated that recombinant apoA-I_M was much more potent than apoA-I in attenuating low-density lipoprotein oxidation. Electron microscopy showed that apoA-I_M/POPC prevented mitochondrial granulation, disorganization and sarcomere contraction band formation indicative of reperfusion injury.

The apoA-I_M/POPC complex thus appears to reduce reperfusion injury under global ischemic conditions, and may therefore have therapeutic application in the reduction of myocardial ischemia.

Keywords: Ischemia reperfusion injury, High-density lipoproteins, Apolipoprotein A-I_Milano, Apolipoprotein A-I, Antioxidant