Modulating Macrophage Polarization as a Therapy for Atherosclerosis
Macrophages are the cells responsible for removing cholesterols from blood vessel walls, to prevent the formation of fatty lesions. Unfortunately they become dysfunctional and inflammatory with age, as a result of rising levels of oxidized cholesterol. This leads to atherosclerosis, an ultimately fatal condition in which lesions grow to the point of weakening and narrowing blood vessels. This condition is strongly affected by inflammation, as macrophages can adopt different behavioral types, known as polarizations, in response to circumstances. Greater inflammatory signaling will drive more macrophages to adopt the aggressive M1 phenotype, focused on destroying pathogens, rather than the regenerative M2 phenotype that is more useful in removing cholesterol from blood vessel walls.
A number of groups are working on ways to force macrophages to adopt a specific phenotype, overriding their usual reaction to surrounding circumstances. In the research here, an approach is demonstrated to be beneficial in a mouse model of atherosclerosis, presumably by putting more macrophages back to work in lesions, clearing out lipids rather than flailing and adding to the inflammatory environment.
Atherosclerosis-related cardiovascular disease is still the predominant cause of death worldwide. Araloside C (AsC), a natural saponin, exerts extensive anti-inflammatory properties. In this study, we explored the protective effects and mechanism of AsC on macrophage polarization in atherosclerosis in vivo and in vitro. Using a high-fat diet (HFD)-fed ApoE-/- mouse model and RAW 264.7 macrophages exposed to oxidized LDL, AsC was evaluated for its effects on polarization and autophagy.
AsC significantly reduced the plaque area in atherosclerotic mice and lipid accumulation in oxidized-LDL-treated macrophages, promoted M2 phenotype macrophage polarization, increased the number of autophagosomes and modulated the expression of autophagy-related proteins. Moreover, the autophagy inhibitor 3-methyladenine and BECN1 siRNA obviously abolished the antiatherosclerotic and M2 macrophage polarization effects of AsC. Mechanistically, AsC targeted Sirt1 and increased its expression, and this increase in expression was associated with increased autophagy and M2 phenotype polarization. Altogether, AsC attenuates foam cell formation and lessens atherosclerosis by modulating macrophage polarization via Sirt1-mediated autophagy.