title: Oral administration of L-mR18L, a single domain cationic amphipathic helical peptide, inhibits lesion formation in ApoE null mice.
abstract: We have shown that Ac-hE18A-NH₂, a dual-domain cationic apolipoprotein-mimetic peptide, reduces plasma cholesterol levels in dyslipidemic mice. Two single-domain cationic peptides based on the lytic class L peptide 18L were developed to test the hypothesis that a single-domain cationic amphipathic peptide can reduce atherosclerosis in apolipoprotein (apo)E null mice when orally administered. To incorporate anti-inflammatory properties, aromatic residues were clustered in the nonpolar face similar to peptide 4F, resulting in modified 18L (m18L). To reduce lytic properties, the Lys residues of 18L were replaced with Arg with the resulting peptide called modified R18L (mR18L). Biophysical studies showed that mR18L had stronger interactions with lipids than did m18L. Peptide mR18L was also more effective than m18L in promoting LDL uptake by HepG2 cells. ApoE null mice received normal chow or chow containing m18L or mR18L for six weeks. A significant reduction in plasma cholesterol and aortic sinus lesion area was seen only in the mR18L group. Plasma from mice administered mR18L, unlike those from the control and m18L groups, did not enhance monocyte adhesion to endothelial cells. Thus oral administration of mR18L reduces plasma cholesterol and lesion formation and inhibits monocyte adhesion.
authors.affiliation: Atherosclerosis Research Unit, Department of Medicine, University of Alabama, Birmingham, AL, USA.
authors.forename: Shaila P
authors.initials: SP
authors.lastname: Handattu
authors.forename: Geeta
authors.initials: G
authors.lastname: Datta
authors.forename: Richard M
authors.initials: RM
authors.lastname: Epand
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Epand
authors.forename: Mayakonda N
authors.initials: MN
authors.lastname: Palgunachari
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Mishra
authors.forename: Candyce E
authors.initials: CE
authors.lastname: Monroe
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Keenum
authors.forename: Manjula
authors.initials: M
authors.lastname: Chaddha
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.forename: David W
authors.initials: DW
authors.lastname: Garber
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001014:Aortic Aneurysm / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002412:Cations; D002448:Cell Adhesion / Q000187:drug effects; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D000893:Anti-Inflammatory Agents; D002412:Cations; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010455:Peptides; C582615:mR18L peptide; C018357:peptide L; D001120:Arginine; D002784:Cholesterol; D008239:Lysine