Proinflammatory Action of a New Electronegative Low-Density Lipoprotein Epitope

Author(s):Show less -

Santo Faulin, Tanize do Espirito ^[1] ; Kazuma, Soraya Megumi ^[1] ; Tripodi, Gustavo Luis ^[1] ; Cavalcante, Marcela Frota ^[1] ; Wakasuqui, Felipe ^[1] ; Pinto Oliveira, Cristiano Luis ^[2] ; de Souza Degenhardt, Maximilia Frazao ^[2] ; Michaloski, Jussara ^[3] ; Giordano, Ricardo Jose ^[3] ; Jacon Ketelhuth, Daniel Francisco ^{[4, 5]} ; Parra Abdalla, Dulcineia Saes ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Phys, Dept Expt Phys, BR-05508090 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Chem, Dept Biochem, BR-05508000 Sao Paulo, SP - Brazil

^[4] Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Mol Med, S-17164 Stockholm - Sweden

^[5] Univ Southern Denmark, Inst Mol Med, Dept Cardiovasc & Renal Res, DK-5000 Odense - Denmark

• Document type: Journal article
• Source: BIOMOLECULES; v. 9, n. 8 AUG 2019.
• Web of Science Citations: 1

Abstract

The electronegative low-density lipoprotein, LDL (-), is an endogenously modified LDL subfraction with cytotoxic and proinflammatory actions on endothelial cells, monocytes, and macrophages contributing to the progression of atherosclerosis. In this study, epitopes of LDL (-) were mapped using a phage display library of peptides and monoclonal antibodies reactive to this modified lipoprotein. Two different peptide libraries (X6 and CX8C for 6- and 8-amino acid-long peptides, respectively) were used in the mapping. Among all tested peptides, two circular peptides, P1A3 and P2C7, were selected based on their high affinities for the monoclonal antibodies. Small-angle X-ray scattering analysis confirmed their structures as circular rings. P1A3 or P2C7 were quickly internalized by bone marrow-derived murine macrophages as shown by confocal microscopy. P2C7 increased the expression of TNF alpha, IL-1 beta and iNOS as well as the secretion of TNF alpha, CCL2, and nitric oxide by murine macrophages, similar to the responses induced by LDL (-), although less intense. In contrast, P1A3 did not show pro-inflammatory effects. We identified a mimetic epitope associated with LDL (-), the P2C7 circular peptide, that activates macrophages. Our data suggest that this conformational epitope represents an important danger-associated molecular pattern of LDL (-) that triggers proinflammatory responses. (AU)

• FAPESP's process: 12/51316-5 - Study of the activity of biodrugs, PPARs agonists and natural products with therapeutic potential in atherosclerosis
• Grantee: Dulcineia Saes Parra Abdalla
• Support Opportunities: Research Projects - Thematic Grants