| First Author | Tao W | Year | 2020 |
| Journal | Sci Transl Med | Volume | 12 |
| Issue | 553 | PubMed ID | 32718990 |
| Mgi Jnum | J:292369 | Mgi Id | MGI:6448896 |
| Doi | 10.1126/scitranslmed.aay1063 | Citation | Tao W, et al. (2020) siRNA nanoparticles targeting CaMKIIgamma in lesional macrophages improve atherosclerotic plaque stability in mice. Sci Transl Med 12(553) |
| abstractText | 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-Ca(2+)/calmodulin-dependent protein kinase gamma (CaMKIIgamma). CaMKIIgamma 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 CaMKIIgamma 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. |
