Structural requirements for antioxidative and anti-inflammatory properties of apolipoprotein A-I mimetic peptides.
ABSTRACT Recently, attention has been focused on pharmacological treatments that increase HDL cholesterol to prevent coronary artery disease. Despite three decades of extensive research of human apolipoprotein A-I (apoA-I), the major protein component of HDL, the molecular basis for its antiatherogenic and anti-inflammatory functions remain elusive. Another protein component of HDL, apoA-II, has structural features similar to those of apoA-I but does not possess atheroprotective properties. To understand the molecular basis for the effectiveness of apoA-I, we used model synthetic peptides. We designed analogs of the class A amphipathic helical motif in apoA-I that is responsible for solubilizing phospholipids. None of these analogs has sequence homology to apoA-I, but all are similar in their lipid-associating structural motifs. Although all of these peptide analogs interact with phospholipids to form peptide:lipid complexes, the biological properties of these analogs are different. Physical-chemical and NMR studies of these peptides have enabled the delineation of structural requirements for atheroprotective and anti-inflammatory properties in these peptides. It has been shown that peptides that interact strongly with lipid acyl chains do not have antiatherogenic and anti-inflammatory properties. In contrast, peptides that associate close to the lipid head group (and hence do not interact strongly with the lipid acyl chain) are antiatherogenic and anti-inflammatory. Understanding the structure and function of apoA-I and HDL through studies of the amphipathic helix motif may lead to peptide-based therapies for inhibiting atherosclerosis and other related inflammatory lipid disorders.
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ABSTRACT: Modulation of the reverse cholesterol transport (RCT) pathway may provide a therapeutic target for the prevention and treatment of atherosclerotic cardiovascular disease (CVD). In the present study, we evaluated a novel 26-amino acid apolipoprotein mimetic peptide (ATI-5261) designed from the carboxyl terminal of apoE, in its ability to mimic apoA-I functionality in RCT in vitro. Our data shows that nascent HDL-like (nHDL) particles generated by incubating cells over-expressing ABCA1 with ATI-5261 increases the rate of specific ABCA1 dependent lipid efflux, with high affinity interactions with ABCA1. We also show that these nHDL particles interact with membrane micro-domains in a manner similar to nHDL apoA-I. These nHDL particles then interact with the ABCG1 transporter and are remodeled by plasma HDL-modulating enzymes. Finally, we show that these mature HDL-like particles are taken up by SR-BI for cholesterol delivery to liver cells. This ATI-5621-mediated process mimics apoA-I and may provide a means to prevent cholesterol accumulation in the artery wall. In this study, we propose an integrative physiology approach of HDL biogenesis with the synthetic peptide ATI-5261. These experiments provide new insights for potential therapeutic use of apolipoprotein mimetic peptides.Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 08/2014; · 4.50 Impact Factor
- The Journal of Lipid Research 08/2014; · 4.73 Impact Factor
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ABSTRACT: It has been demonstrated that peripheral injection of anti-amyloid-β (Aβ) antibodies to patients with Alzheimer's disease (AD) and AD transgenic mice facilitate Aβ clearance. We hypothesized that peripheral circulating Aβ-binding proteins also possess the ability to enhance Aβ clearance and the levels of circulating Aβ-binding proteins could serve as early AD biomarkers. Circulating Aβ-binding proteins were isolated from plasma and identified by LC-MS/MS. Their levels were compared among non-demented individuals without AD family history (ND), with AD family history (ND-FH), and patients with mild AD. The results showed that most of the identified Aβ-binding proteins were apolipoproteins, i.e., apoA-I, apoB-100, apoC-III, and apoE. Aβ bound preferentially to apoA-I-enriched HDL, followed by apoC-III- and apoE-enriched VLDL, and bound less favorably to apoB-100-enriched LDL. Levels of apoA-I were reduced in AD patients and could be used to discriminate AD from ND groups (AUC: 0.93); whereas levels of apoC-III were reduced in both ND-FH and AD groups and could be used to differentiate ND-FH from ND individuals (AUC: 0.81). Both the levels of apoA-1 and apoC-III positively correlated with CASI and MMSE scores. In conclusion, these results suggest that plasma apoA-I could be a sensitive AD biomarker and individuals with low plasma levels of apoC-III are at risk for AD.Journal of Alzheimer's disease: JAD 03/2014; · 3.61 Impact Factor