Hydroxysafflor yellow A, a natural food pigment, ameliorates atherosclerosis in <scp>ApoE</scp> ^−/− mice by inhibiting the <scp>SphK1</scp> / <scp>S1P</scp> / <scp>S1PR3</scp> pathway

Atherosclerosis (AS) is the pathologic basis of many cardiovascular diseases (CVDs). Hydroxysafflor yellow A (HSYA) is a valuable natural food pigment that has been reported to have significant health-promoting abilities. However, the anti-AS efficacy and mechanisms of HSYA have not yet been characterized. Here, we found that treatment of apolipoprotein A (ApoE) knockout (ApoE^-/-) mice with HSYA markedly ameliorated atherosclerosis evidenced by decreased levels of lipids, sphingosine-1-phosphate (S1P), inflammatory factors, oxidative stress, vascular endothelial permeability, and endothelial damage. Moreover, mechanistic studies revealed that HSYA treatment downregulated the expression of aortic sphingosine kinase 1 (SphK1), sphingosine-1-phosphate receptor 3 (S1PR3), Ras homolog family member A (RhoA), Rho-associated coiled-coil containing protein kinase (ROCK), and filamentous actin (F-actin). The results of administration with HSYA reversed the effects of SphK1 agonist and S1PR3 agonist on oxidized low-density lipoprotein (ox-LDL)-induced vascular endothelial cell migration ability and F-actin expression, and decreased RhoA/ROCK protein expression further confirmed the conclusion that HSYA reduced vascular endothelial permeability by modulating the SphK1/S1P/S1PR3/RhoA/ROCK signaling pathway, thereby exerting anti-atherosclerotic effects. Overall, this study indicated that HSYA might be a therapeutic candidate for the treatment of AS.