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

Marquez-Sanchez, A. C.; Manzanares-Guzman, A.; Carriles-Jaimes, R.; Sanchez-Segura, L.; Colin-Castelan, D.; Kamen, D.; Koltsova, E. K.; Maritnez-Antonio, A.; Rodriguez-Rios, D.; Romo-Morales, G. d. C.; Lund, G.; Zaina, S.

doi:10.1101/2023.08.22.554347

bioRxiv · 10.1101/2023.08.22.554347

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

Marquez-Sanchez, A. C.·Manzanares-Guzman, A.·Carriles-Jaimes, R.·Sanchez-Segura, L.·Colin-Castelan, D.·Kamen, D.·Koltsova, E. K.·Maritnez-Antonio, A.·Rodriguez-Rios, D.·Romo-Morales, G. d. C.·Lund, G.·Zaina, S.

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Abstract

Background 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.

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Marquez-Sanchez, A. C., Manzanares-Guzman, A., Carriles-Jaimes, R., Sanchez-Segura, L., Colin-Castelan, D., Kamen, D., Koltsova, E. K., Maritnez-Antonio, A., Rodriguez-Rios, D., Romo-Morales, G. d. C., Lund, G., Zaina, S.. 2023-08-22. Macrophage-targeted DNA methyltransferase inhibitor SGI-1027 decreases atherosclerosis in ApoE-null mice. https://doi.org/10.1101/2023.08.22.554347

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