Poliumoside attenuates endothelial senescence and atherosclerosis by regulating MKRN2-mediated autophagy via the PI3K/AKT/ mTOR pathway.

Poliumoside reduced senescence marker expression and SA-β-gal-positive area in aortic tissue of ApoE-/- mice, attenuating vascular senescence and atherosclerotic lesions.

• Compared with ApoE-/- control group, Pol-treated animals showed reduced senescence marker expression in aortic tissue.
• SA-β-gal-positive area was reduced in aortic tissue following Pol treatment.
• Pol alleviated autophagy dysfunction in vivo, contributing to attenuation of atherosclerotic lesions.
• The study used an ApoE-/- mouse model to assess in vivo atherosclerosis and vascular senescence.

Poliumoside suppressed upregulation of senescence markers p16, p21, and p53 in H₂O₂-induced senescent HUVECs.

• H₂O₂ was used to induce senescence in Human Umbilical Vein Endothelial Cells (HUVECs) in vitro.
• Pol treatment suppressed upregulation of p16, p21, and p53 in senescent HUVECs.
• Pol also decreased Senescence-Associated Secretory Phenotype (SASP) levels in senescent HUVECs.
• Pol reduced oxidative stress in the H₂O₂-induced senescence model.

Poliumoside improved autophagy dysfunction in senescent HUVECs.

• H₂O₂-induced senescence suppressed autophagy in HUVECs, and Pol treatment mitigated this suppression.
• Pol improved autophagy dysfunction both in vitro in HUVECs and in vivo in aortic tissue of ApoE-/- mice.
• Restoration of autophagy function was associated with the protective effects of Pol against cellular senescence.

Poliumoside bound to MKRN2 and inhibited phosphorylation of the PI3K/AKT/mTOR pathway, mitigating H₂O₂-induced suppression of autophagy.

• Mechanistic studies showed Pol directly bound to Makorin Ring Finger Protein 2 (MKRN2).
• Pol inhibited phosphorylation of the PI3K/AKT/mTOR pathway.
• Inhibition of the PI3K/AKT/mTOR pathway by Pol mitigated H₂O₂-induced suppression of autophagy.
• The interaction with MKRN2 was identified as the upstream mechanistic link connecting Pol to PI3K/AKT/mTOR pathway regulation.

siRNA-mediated downregulation of MKRN2 reversed the effects of Poliumoside on the PI3K/AKT/mTOR signaling pathway, autophagy, and senescence protection.

• siRNA knockdown of MKRN2 reversed Pol-induced effects on the PI3K/AKT/mTOR signaling pathway.
• MKRN2 downregulation also reversed the effects of Pol on autophagy restoration.
• siRNA-mediated MKRN2 knockdown attenuated the protective effect of Pol against cellular senescence.
• These findings confirmed that MKRN2 is necessary for the anti-senescence mechanism of Pol.

Endothelial senescence contributes to the development and progression of atherosclerosis, and oxidative stress and inflammation are major triggers of senescence.

• The study identified endothelial senescence as a contributing factor to atherosclerosis development and progression.
• Oxidative stress and inflammation were identified as major triggers of endothelial senescence.
• Poliumoside has previously been shown to attenuate oxidative stress and inflammation.
• The role of Pol in HUVEC senescence was previously elusive prior to this study.