Vascular cellular senescence in human atherosclerosis: The critical modulating roles of CDKN2A and CDK4/6 signaling pathways
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View abstract on PubMed
Summary
This summary is machine-generated.Vascular cellular senescence drives aging and atherosclerosis. Targeting the CDKN2A and CDK4/6 pathway in endothelial cells shows promise for preventing vascular aging and atherosclerosis.
Area Of Science
- Cardiovascular Biology
- Cellular Senescence
- Molecular Medicine
Background
- Vascular cellular senescence is a key driver of vascular aging and atherosclerosis.
- Therapeutic strategies targeting vascular senescence offer potential for treating atherosclerosis.
Purpose Of The Study
- To investigate the role of differentially expressed genes (DEGs) in vascular senescence and atherosclerosis.
- To identify key molecular pathways involved in endothelial cell senescence in atherosclerotic lesions.
Main Methods
- Transcriptomic analysis of human atherosclerotic lesions and normal vessels.
- Oxidized low-density lipoprotein (Ox-LDL) induced human umbilical vein endothelial cells (HUVECs) and ApoE-/- mice models.
- Venn diagrams for DEG screening, CDKN2A knockdown, and CDK4/6 inhibitor (palbociclib) treatment.
- Immunohistochemistry for β-galactosidase, CDKN2A, and CD31 in human and mouse tissues.
Main Results
- CDKN2A was identified as a key senescence-related DEG, upregulated in atherosclerotic lesions.
- Upregulated CDKN2A suppressed CDK4/6, leading to cell-cycle arrest, reduced viability, inhibited migration, and increased senescence markers (ROS, β-galactosidase) in HUVECs.
- CDKN2A knockdown ameliorated these effects, while palbociclib exacerbated them.
- Endothelial cellular senescence and elevated CDKN2A expression were confirmed in vivo in atherosclerotic lesions.
- Palbociclib treatment worsened vascular senescence and atherogenesis in mice.
Conclusions
- Endothelial cellular senescence is a hallmark of atherosclerotic lesions.
- The CDKN2A and CDK4/6 pathway is actively involved in endothelial senescence and atherogenesis.
- Modulating the CDKN2A/CDK4/6 pathway represents a potential therapeutic target for preventing vascular aging and atherosclerosis.
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