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Senescence-dependent regulation of type 1 plasminogen activator inhibitor in human vascular endothelial cells
P Comi1, R Chiaramonte, J A Maier
1Dipartimento di Scienze e Tecnologie Biomediche-Ospedale San Raffaele, Università di Milano, Italy.
Insights
Type 1 plasminogen activator inhibitor (PAI-1) is constitutively high in senescent endothelial cells and correlates with interleukin-1 alpha upregulation. PAI-1 may serve as a marker for endothelial cell senescence.
Area of Science:
- Cellular senescence
- Endothelial biology
- Thrombosis
Background:
- Type 1 plasminogen activator inhibitor (PAI-1) is a key inhibitor of fibrinolysis, elevated in prothrombotic states.
- Endothelial cell aging in vitro mirrors changes seen in aging and atherosclerosis in vivo.
Purpose of the Study:
- To investigate the expression of PAI-1 in endothelial cells at different stages of senescence.
- To determine if PAI-1 can serve as a marker for endothelial cell senescence.
Main Methods:
- Examined PAI-1 mRNA and protein levels in endothelial cells across various population doublings.
- Assessed PAI-1 inducibility by interleukin-1 alpha and TPA in senescent cells.
- Compared PAI-1 expression in senescent endothelial cells with senescent fibroblasts.
Main Results:
- Senescent endothelial cells exhibit high, constitutive PAI-1 mRNA and protein levels.
- PAI-1 in senescent endothelial cells is not inducible by exogenous interleukin-1 alpha or TPA.
- Elevated PAI-1 levels correlate with increased interleukin-1 alpha, a hallmark of endothelial cell senescence.
- PAI-1 expression is not increased in senescent fibroblasts lacking interleukin-1 alpha overexpression.
Conclusions:
- PAI-1 expression is a potential marker for endothelial cell senescence.
- Multiple pathways regulate aging in human fibroblasts and endothelial cells.
Abstract:
Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor plasminogen activator and has been found to be increased in a number of clinical conditions generally defined as prothrombotic. Since in aging and in atherosclerosis the changes observed in the endothelium resemble those of in vitro aged endothelial cells, we have examined the expression of PAI-1 in cells at different population doublings. In senescent endothelial cells, PAI-1 mRNA and protein are constitutively high, but uninducible by exogenous interleukin 1 alpha as well as by the phorbol ester TPA. Interestingly the increase of PAI-1 levels correlates with the upregulation of interleukin 1 alpha, which characterizes endothelial cell senescence. Since PAI-1 expression is not increased in young cells made nondividing by contact inhibition, we anticipate that PAI-1 expression can be used as an appropriate marker of endothelial senescence. Moreover, PAI-1 was not upregulated in senescent or in progeric human fibroblasts, which do not overexpress interleukin 1 alpha, thus suggesting that multiple pathways may exist to regulate aging of human fibroblasts and endothelial cells.