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Rapid reversal of endothelial dysfunction in hypercholesterolemic apolipoprotein E-null mice by recombinant apolipoprotein A-I_Milano-phospholipid complex

Sanjay Kaul, MD^*,,*, Bryan Coin, BS^*,, Amir Hedayiti, MD^*,, Juliana Yano, BS^*,, Bojan Cercek, MD, PhD^*,, Kuang-Y. Chyu, MD, PhD^*, and Prediman K. Shah, MD^*,

^* Vascular Physiology and Thrombosis Research Laboratory of the Atherosclerosis Research Center, Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California, USA
David Geffen School of Medicine, University of California, Los Angeles, California, USA

Manuscript received March 11, 2004; revised manuscript received June 2, 2004, accepted June 7, 2004.

^* Reprint requests and correspondence: Dr. Sanjay Kaul, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048 (Email: kaul{at}cshs.org).

OBJECTIVES: In this study, we examined whether a reconstituted high-density lipoprotein (HDL) utilizing recombinant apolipoprotein A-I_Milano (apo A-I_M)/phospholipid complex (PC) could restore normal endothelial function in hypercholesterolemic apolipoprotein (apo) E-null mice.

BACKGROUND: We have previously shown antiatherosclerotic and vasculoprotective effects of recombinant apo A-I_M.

METHODS: A perfused vessel preparation was used to examine vascular responses in control wild-type, untreated, and treated apo E-null mice. Aortic tissue cholesterol content and platelet aggregation were also measured.

RESULTS: Endothelium-dependent vasodilator responses to acetycholine were significantly inhibited in untreated apo E-null mice compared with control wild-type mice (p < 0.001). Treatment of the mice for five weeks with once every-other-day intravenous bolus injections of apo A-I_M/PC restored endothelium-dependent dilation in a dose-dependent manner (p < 0.01 at 80 mg/kg dose). The improvement in endothelial function was associated with a reduction in aortic cholesterol content and reduced platelet aggregability and occurred despite severe and persistent hypercholesterolemia. Neither treatment with free protein nor phospholipid carrier alone produced any significant effects. We performed additional experiments in vitro in isolated rabbit carotid arteries to compare the effects on lysophosphatidylcholine (LPC)-induced endothelial dysfunction. Treatment with apo A-I_M/PC prevented impairment of endothelium-dependent vasodilator responses to acetylcholine to a greater degree than either wild-type apo A-I or plasma-derived HDL.

CONCLUSIONS: Our results indicate a rapid improvement in endothelial dysfunction with recombinant apo A-I_M/PC that is associated with mobilization of tissue cholesterol. Taken together with previously established antiatherosclerotic and antithrombotic effects, these findings suggest significant vasculoprotective effects with apo A-I_M/PC therapy.

Abbreviations and Acronyms   apo = apolipoprotein   apo A-IM = apo A-IMilano   EDNO = endothelium-derived nitric oxide   HDL = high-density lipoprotein   LPC = L--phosphatidylcholine palmitoyl   PC = phospholipid complex   WT = wild-type

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