Research ArticleAtherosclerosis

siRNA nanoparticles targeting CaMKIIγ in lesional macrophages improve atherosclerotic plaque stability in mice

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Science Translational Medicine  22 Jul 2020:
Vol. 12, Issue 553, eaay1063
DOI: 10.1126/scitranslmed.aay1063

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Perturbing plaque macrophages

Macrophages in atherosclerotic lesions promote inflammation and plaque progression and are an attractive therapeutic target. Here, Tao et al. used nanoparticles to inhibit pro-atherogenic macrophages by siRNA targeting Ca2+/calmodulin-dependent protein kinase γ. Nanoparticle treatment induced phagocytosis of apoptotic cells in plaques and promoted plaque stability, reducing necrotic area and increasing fibrous cap thickness in a mouse model of atherosclerosis. This study establishes proof of concept for siRNA nanoparticles targeting lesional macrophages as a treatment for atherosclerosis.

Abstract

Atherosclerotic lesional macrophages express molecules that promote plaque progression, but lack of mechanisms to therapeutically target these molecules represents a major gap in translational cardiovascular research. Here, we tested the efficacy of a small interfering RNA (siRNA) nanoparticle (NP) platform targeting a plaque-destabilizing macrophage molecule—Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ). CaMKIIγ becomes activated in advanced human and mouse plaque macrophages and drives plaque necrosis by suppressing the expression of the efferocytosis receptor MerTK. When macrophage-targeted siCamk2g NPs were administered to Western diet–fed Ldlr−/− mice, the atherosclerotic lesions showed decreased CaMKIIγ and increased MerTK expression in macrophages, improved phagocytosis of apoptotic cells (efferocytosis), decreased necrotic core area, and increased fibrous cap thickness—all signs of increased plaque stability—compared with mice treated with control siRNA NPs. These findings demonstrate that atherosclerosis-promoting genes in plaque macrophages can be targeted with siRNA NPs in a preclinical model of advanced atherosclerosis.

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