Published Online
on September 7, 2004

A more recent version of this article appeared on September 21, 2004

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Submitted on May 4, 2004
Revised on July 15, 2004
Accepted on July 21, 2004

Differential Effects of Apolipoprotein A-I-Mimetic Peptide on Evolving and Established Atherosclerosis in Apolipoprotein E-Null Mice

Xiaojun Li MD, PhD, Kuang-Yuh Chyu MD, PhD, Jose R. Faria Neto MD, PhD, Juliana Yano BS, Nitya Nathwani MD, Carmel Ferreira BS, Paul C. Dimayuga PhD, Bojan Cercek MD, PhD, Sanjay Kaul MD^*, and Prediman K. Shah MD

From the Atherosclerosis Research Center, Division of Cardiology, Department of Medicine and Burns and Allen Research Institute, Cedars-Sinai Medical Center and David Geffen School of Medicine at UCLA, Los Angeles, Calif.

^* To whom correspondence should be addressed. E-mail: shahp{at}cshs.org.

Background--Apolipoprotein (apo) A-I and apoA-I-mimetic peptides showed promise to prevent atherosclerosis development. Using a bypassed vein graft model in apoE-null mice, we evaluated the effects of oral or intraperitoneal administration of an apoA-I-mimetic peptide on evolving atherosclerotic lesions in the vein graft and compared such effects on the established atherosclerotic lesions in aortic sinus in the same mice.

Methods and Results--We used apoE-null mice in which a segment of inferior vena cava was grafted into the right carotid artery at 16 weeks of age. Native aortic atherosclerotic lesions (established atherosclerosis) and vein-graft atherosclerotic lesions (evolving atherosclerosis) were assessed 4 weeks after daily oral (0.3 mg/mL) or intraperitoneal (50 µg in 200 µL saline) administration of an apoA-I-mimetic peptide, D4F. Mice receiving saline or water without D4F served as controls. Both oral and intraperitoneal administration of D4F reduced vein-graft atherosclerotic (evolving lesions) plaque size by 43% and 42%, plaque lipid by 70% and 49%, and macrophage immunoreactivity by 63% and 62%, respectively, compared with controls. In contrast, D4F had no effect on the native aortic sinus atherosclerotic lesions (established lesions).

Conclusions--Oral and intraperitoneal administration of the apoA-I-mimetic peptide D4F significantly reduced rapidly evolving atherosclerotic lesions in vein grafts but not established atherosclerotic lesions in aortic sinus. These observations suggest that the type of atherosclerotic lesions and the time of initiation during the course of lesion evolution modulate the beneficial effects of apoA-I-mimetic peptides on atherosclerosis.

Key words: atherosclerosis • apolipoproteins • peptides

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