Guan-Xin-Kang and its active compound astragaloside IV improve atherosclerosis through extracellular signal-regulated kinase 5-mediated macrophage efferocytosis

To investigate the effects and potential mechanisms of Guan-Xin-Kang (GXK) and its active component Astragaloside IV (AS-IV) in atherosclerosis. Using GXK and AS-IV intervention on high-fat diet-fed macrophage-specific ERK5 knockout LDLR −/− mice (ERK5-MKO/LDLR −/− ) and non-transgenic littermate control LDLR−/− mice (NLC/LDLR −/− ), we assessed peripheral blood lipid levels, aortic lesion area, cellular composition, and the expression of efferocytosis-related genes. GXK significantly reduced blood lipid levels, atherosclerotic plaque area, expression of the macrophage marker MAC3, and increased the expression of the smooth muscle cell marker SMA. It also regulated the expression of efferocytosis-related genes Axl, PPARD, TIM4, and C1QA, regardless of ERK5 knockout. In ERK5 knockout mice, the effects of AS-IV on macrophage marker MAC3, smooth muscle cell marker SMA, and efferocytosis-related genes Axl, PPARD, TIM4, and C1QA were abolished. This study confirms the therapeutic effects of GXK on atherosclerotic mice and reveals that GXK targets additional pathways beyond ERK5, whereas its active component AS-IV may specifically target ERK5.