Macrophage-targeted DNA methyltransferase inhibitor SGI-1027 decreases atherosclerosis in ApoE-null mice

Author:

Márquez-Sánchez Ana Cristina,Manzanares-Guzmán Alejandro,Carriles-Jaimes Ramón,Sánchez-Segura Lino,Colín-Castelán Dannia,Kamen Dan,Koltsova Ekaterina K.,Martínez-Antonio Agustino,Rodríguez-Ríos Dalia,del Carmen Romo-Morales Gloria,Lund Gertrud,Zaina Silvio

Abstract

AbstractBackground and aimsCorrection of vascular DNA hypermethylation may slow atherogenesis. We tested the anti-inflammatory and anti-atherogenic activity of macrophage-targeted DNA methyltransferase (DNMT) inhibitor SGI-1027.Methods, ResultsSGI-1027 was encapsulated into human serum albumin (HSA) nanoparticles (HSANP) functionalized with the PP1 peptide, a macrophage scavenger receptor 1 ligand, fused to a FLAG epitope (S-HSANP-FLAGPP1). Nanoparticle physico-chemical characteristics predicted good marginalization towards the vascular wall, although SGI-1027 encapsulation efficiency was relatively low (∼23%). S-HSANP-FLAGPP1 were rapidly internalized compared to non-functionalized and, surprisingly, functionalized void controls, and induced a shift towards an anti-inflammatory profile of secreted cytokines in human THP-1 macrophages. S-HSANP-FLAGPP1 colonized the atheroma and induced a significant ∼44% reduction of atherosclerosis burden in the aortic tree of ApoE-null mice compared to controls. A reduction in aortic root atherosclerosis was observed, although primarily induced by HSANP irrespective of loading or functionalization. No alteration of body weight, non-vascular tissue gross histology, plasma glucose, triglyceride or cholesterol were observed. HSA whether free or structured in nanoparticles, induced a 3-4-fold increase in HDL compared to vehicle.ConclusionsWe confirm that DNMT inhibition is anti-atherogenic and provide proof of principle that targeted HSANP are effective carriers for those molecules. SGI-1027 displayed a novel anti-inflammatory activity that is independent of cell proliferation and therefore likely unrelated to DNMT inhibition. HDL elevation may represent an additional advantage of HSA-based nanocarriers.

Publisher

Cold Spring Harbor Laboratory

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