Plasminogen activator inhibitor 1 promotes aortic aging–like pathophysiology in humans and mice

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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.

Authors

Alireza Khoddam, Anthony Kalousdian, Mesut Eren, Saul Soberanes, Andrew Decker, Elizabeth J. Lux, Benjamin W. Zywicki, Brian Dinh, Bedirhan Boztepe, Baljash S. Cheema, Carla M. Cuda, Hiam Abdala-Valencia, Arun Sivakumar, Toshio Miyata, Lisa D. Wilsbacher, Douglas E. Vaughan