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Published on: September 28, 2015
Plasminogen activator inhibitor 1 promotes aortic aging-like pathophysiology in humans and mice
Alireza Khoddam1, Anthony Kalousdian1, Mesut Eren1
1Feinberg Cardiovascular and Renal Research Institute.
Insights
Reducing plasminogen activator inhibitor 1 (PAI-1) protects against cardiovascular aging. PAI-1 inhibition is a promising strategy to mitigate age-related cardiovascular disease (CVD).
Area of Science:
- Cardiovascular Biology
- Aging Research
- Vascular Medicine
Background:
- Plasminogen activator inhibitor 1 (PAI-1), encoded by SERPINE1, is implicated in age-related cardiovascular disease (CVD).
- Human genetic variants reducing SERPINE1 function confer protection against aging and cardiometabolic dysfunction.
- Understanding PAI-1's role in vascular aging is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the impact of reduced PAI-1 levels on cardiovascular aging using a mouse model.
- To elucidate the molecular mechanisms underlying PAI-1's vascular-protective effects.
- To evaluate the therapeutic potential of PAI-1 inhibition in mitigating cardiovascular aging.
Main Methods:
- Engineered a mouse model (Serpine1TA700/+) mimicking human SERPINE1 loss-of-function variant.
- Assessed cardiovascular responses under vascular stress (l-NAME) and PAI-1 overexpression.
- Utilized single-cell transcriptomics to analyze aortic gene expression and cellular composition.
- Investigated the effects of pharmacological PAI-1 inhibition.
Main Results:
- Serpine1TA700/+ mice exhibited increased lifespan and improved cardiovascular function under stress, including lower pulse wave velocity (PWV) and systolic blood pressure (SBP).
- PAI-1 overexpression accelerated cardiovascular aging phenotypes.
- Single-cell transcriptomics revealed downregulation of extracellular matrix regulators (Ccn1, Itgb1) and enrichment of plastic smooth muscle cells in Serpine1TA700/+ aortas.
- Pharmacological PAI-1 inhibition normalized SBP and reversed l-NAME-induced PWV elevation.
Conclusions:
- Reduced PAI-1 levels confer significant protection against cardiovascular aging and associated pathologies.
- PAI-1 inhibition emerges as a potent therapeutic strategy for mitigating age-related CVD.
- The study highlights a vascular-protective mechanism involving extracellular matrix regulation and smooth muscle cell plasticity.
Abstract:
Plasminogen activator inhibitor 1 (PAI-1), encoded by SERPINE1, contributes to age-related cardiovascular disease (CVD) and other aging-related pathologies. Humans with a heterozygous loss-of-function SERPINE1 variant exhibit protection against aging and cardiometabolic dysfunction. We engineered a mouse model mimicking the human mutation (Serpine1TA700/+) and compared cardiovascular responses with WT littermates. Serpine1TA700/+ mice lived 17% longer than did littermate control mice. Under l-NG-nitro-arginine methyl ester-induced (l-NAME-induced) vascular stress, Serpine1TA700/+ mice exhibited diminished pulse wave velocity (PWV), lower systolic blood pressure (SBP), and preserved left ventricular diastolic function compared with controls. Conversely, PAI-1-overexpressing mice had measurements indicating accelerated cardiovascular aging. Single-cell transcriptomics of Serpine1TA700/+ aortas revealed a vascular-protective mechanism with downregulation of the extracellular matrix regulators Ccn1 and Itgb1. Serpine1TA700/+ aortas were also enriched in a cluster of smooth muscle cells that exhibited plasticity. Finally, PAI-1 pharmacological inhibition normalized SBP and reversed l-NAME-induced PWV elevation. These findings demonstrate that PAI-1 reduction protects against cardiovascular aging-related phenotypes, while PAI-1 excess promotes vascular pathological changes. Taken together, PAI-1 inhibition represents a promising strategy to mitigate age-related CVD.
