Subendothelial retention of
apolipoprotein B100-containing
lipoprotein, such as
low-density lipoprotein (
LDL), is the initial step of
atherogenesis. Activation of autophagy exhibits beneficial effects for the treatment of
atherosclerosis. In our previous study, we demonstrated that
hyperglycemia suppressed autophagic degradation of
caveolin-1, which in turn resulted in acceleration of caveolae-mediated
LDL transcytosis across endothelial cells and
lipid retention. Therefore, targeting the crossed pathway in autophagy activation and
LDL transcytosis interruption may be a promising antiatherosclerotic strategy. In
metabolic diseases, including
atherosclerosis,
salidroside, a phenylpropanoid
glycoside compound (3,5-dimethoxyphenyl) methyl-β-glucopyranoside), is the most important compound responsible for the therapeutic activities of Rhodiola. However, whether
salidroside suppresses
LDL transcytosis to alleviate
atherosclerosis has not yet been elucidated. In the present study, we demonstrated that
salidroside significantly decreased
LDL transcytosis across endothelial cells.
Salidroside-induced effects were dramatically blocked by AMPK (
adenosine monophosphate-activated
protein kinase) inhibitor (compound c, AMPKα
siRNA) and by overexpression of exogenous
tyrosine-phosphorylated
caveolin-1 using transfected cells with phosphomimicking
caveolin-1 on
tyrosine 14 mutant plasmids (Y14D). Furthermore, we observed that
salidroside promoted autophagosome formation via activating AMPK. Meanwhile, the interaction between
caveolin-1 and LC3B-II, as well as the interaction between active Src (indicated by the phosphorylation of Src on
tyrosine 416) and LC3B-II, was significantly increased, upon stimulation with
salidroside. In addition, both
bafilomycin A1 (a lysosome inhibitor) and an
AMPK inhibitor (compound c) markedly prevented
salidroside-induced autophagic degradation of p-Src and
caveolin-1. Moreover, the phosphorylation of
caveolin-1 on
tyrosine 14 was disrupted due to the downregulation of p-Src and
caveolin-1, thereby directly decreasing
LDL transcytosis by attenuating the number of caveolae on the cell membrane and by preventing caveolae-mediated
LDL endocytosis released from the cell membrane. In
ApoE-/- mice,
salidroside significantly delayed the formation of atherosclerotic lesions. Meanwhile, a significant increase in LC3B, accompanied by attenuated accumulation of the autophagy substrate SQSTM1, was observed in aortic endothelium of
ApoE-/- mice. Taken together, our findings demonstrated that
salidroside protected against
atherosclerosis by inhibiting
LDL transcytosis through enhancing the autophagic degradation of active Src and
caveolin-1.