PCSK9 affects vascular senescence through the SIRT1 pathway

Area of Science:

• Cardiovascular Biology
• Aging Research
• Molecular Medicine

Background:

• Age is a significant risk factor for atherosclerotic cardiovascular disease, increasing vascular intimal thickening, endothelial dysfunction, and thrombosis.
• The precise mechanisms driving age-related vascular injury remain incompletely understood.
• Cellular senescence plays a critical role in age-associated vascular pathologies.

Purpose of the Study:

• To investigate the impact of proprotein convertase subtilin-type kexin 9 (PCSK9) inhibitors on cellular senescence in vascular cells and aged mice.
• To elucidate the role of the sirtuin 1 (SIRT1) pathway in PCSK9-mediated vascular aging.
• To determine if PCSK9 inhibition can mitigate age-related vascular dysfunction.

Main Methods:

• Assessed the effects of PCSK9 inhibitors on human umbilical vein endothelial cells (HUVECs) and senescent mice.
• Utilized lipopolysaccharides (LPS) to induce PCSK9 activation and cellular senescence.
• Measured the expression of senescence markers (P16, P21, P53) and SIRT1 levels.
• Investigated the impact of SIRT1 pathway modulation (inhibition and activation) on PCSK9-induced senescence.

Main Results:

• PCSK9 inhibition delayed senescence in mice and reduced vascular aging.
• LPS induction stimulated PCSK9 activation, increasing senescence markers (P16, P21, P53).
• PCSK9 overexpression accelerated senescence, promoted oxidative stress, and upregulated senescence-related genes.
• Inhibition of SIRT1 attenuated PCSK9's aging effects; SIRT1 activation enhanced senescence.

Conclusions:

• PCSK9 inhibition mitigates vascular senescence by downregulating SIRT1 expression.
• PCSK9 plays a pro-aging role in the vasculature, partly through the SIRT1 pathway.
• Targeting PCSK9 offers a potential therapeutic strategy to combat age-related vascular diseases.