A novel apoA‐I mimetic peptide suppresses atherosclerosis by promoting physiological HDL function in apoE^−/− mice

Abstract

Background and Purpose Apolipoprotein A‐I (apoA‐I) mimetic peptides (AAMPs) are short peptides that can mimic the physiological effects of apoA‐I, including the suppression of atherosclerosis by reversely transporting peripheral cholesterol to the liver. As the hydrophobicity of apoA‐I is considered important for its lipid transport, novel AAMPs were designed and synthesized in this study by gradually increasing the hydrophobicity of the parent peptide, and their anti‐atherosclerotic effects were tested. Experimental Approach Seventeen new AAMPs (P1–P17) with incrementally increased hydrophobicity were designed and synthesized by replacing the amino acids 221–240 of apoA‐I (VLESFKVSFLSALEEYTKKL). Their effects on cholesterol efflux were evaluated. Their cytotoxicity and haemolytic activity were also measured. The in vitro mechanism of the action of the new peptides was explored. Adult apolipoprotein E−/− mice were used to evaluate the anti‐atherosclerotic activity of the best candidate, and the mechanistic basis of its anti‐atherosclerotic effects was explored. Key Results Seventeen new AAMPs (P1–P17) were synthesized, and their cholesterol efflux activity and cytotoxicity were closely related to their hydrophobicity. P12 (FLEKLKELLEHLKELLTKLL) was the best candidate and most strongly promoted cholesterol efflux among the non‐toxic peptides (P1–P12). With its phospholipid affinity, P12 facilitated cholesterol transport through the ATP‐binding cassette transporter A1. In vivo, P12 exhibited prominent anti‐atherosclerotic activity via coupling with HDL. Conclusion and Implications P12 featured adequate hydrophobicity, which ensured its efficient binding with cytomembrane phospholipids, cholesterol and HDL, and provided a basis for its ability to reversely transport cholesterol and treat atherosclerosis.

Novel Broad-Spectrum Antimicrobial Peptide Derived from Anoplin and Its Activity on Bacterial Pneumonia in Mice

“…Additionally, from A-1 to A-8 and from A-9 to A-13, as the hydrophobicity increases, the α-helix content of the new analogues gradually increases, which may also affect their antibacterial activity. This is similar to the conclusions reached in our previous work . If the AMP has higher α-helix content, its antimicrobial activity will be stronger.…”

“…This is similar to the conclusions reached in our previous work. 28 If the AMP has higher α-helix content, its antimicrobial activity will be stronger. In this study, A-8, A-13, A-17, and A-22 had higher α-helix content than the other analogues in 50% TFE, and their antibacterial activities were also higher than that of the other analogues.…”

High Density Lipoprotein Cholesterol Efflux Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological Aspects and Pharmacological Perspectives

“…To date, many apoA-I mimetic peptides have been developed and tested in preclinical studies, showing improvements in atherosclerotic-related parameters, including CEC [ 252 ]; however, none of them have been tested in human studies so far. On the other hand, various clinical trials evaluated the effect of intravenous apoA-I infusion formulations.…”

Very low HDL levels: clinical assessment and management

“…Another apoA-I mimetic peptide synthesized from D-amino acids (D-4F) to LDL receptor null mice on a Western diet made HDL anti-inflammatory and reduced lesions by 79% without altering HDL-C levels (125). Recently, P12 showed efficient binding with cytomembrane phospholipids, cholesterol and HDL, and showed the ability to reverse cholesterol transport and treat atherosclerosis (126). With its phospholipid affinity, P12 facilitated cholesterol transport through the ABCA1.…”