Apolipoprotein A-IMilano/POPC complex attenuates post-ischemic ventricular dysfunction in the isolated rabbit heart.
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 (10 min), pretreated with either apoA-I(M)/POPC (0.45 mg/mL) or vehicle (10 min), subjected to global ischemia (30 min) and reperfused for 60 min. 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.
Marchesi
Marta
M
Department of Pharmacological Sciences, University of Milan, Italy. marta.marchesi@unimi.it
Booth
Erin A
EA
Rossoni
Giuseppe
G
García
Ricardo A
RA
Hill
Knut R
KR
Sirtori
Cesare R
CR
Bisgaier
Charles L
CL
Lucchesi
Benedict R
BR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D004195:Disease Models, Animal; D015227:Lipid Peroxidation / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008297:Male; D008854:Microscopy, Electron; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D010713:Phosphatidylcholines / Q000494:pharmacology*; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology*; D018754:Ventricular Dysfunction / Q000473:pathology / Q000517:prevention & control*
D000975:Antioxidants; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; D011994:Recombinant Proteins; C080631:apolipoprotein A-I Milano; C028694:1-palmitoyl-2-oleoylphosphatidylcholine