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 diseases (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 wild-type littermates. Serpine1TA700/+ mice lived 20% longer than littermate controls. Under L-NG-Nitro-arginine methyl ester (L-NAME)-induced vascular stress, Serpine1TA700/+ mice exhibited diminished pulse wave velocity (PWV), lower systolic hypertension (SBP), and preserved left ventricular diastolic function compared to controls. Conversely, PAI-1-overexpressing mice exhibited measurements indicating accelerated cardiovascular aging. Single cell transcriptomics of Serpine1TA700/+ aortas revealed a vascular-protective mechanism with downregulation of 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