Faculty Collaboration Database

Silencing of PAI-1 using siRNA-lipid nanoparticles reduces thrombosis and prolongs life span in murine models. Blood 2026 Apr 30;147(18):2053-2063

Date

01/26/2026

Pubmed ID

41587091

Pubmed Central ID

PMC12994142

DOI

10.1182/blood.2025029834

Scopus ID

2-s2.0-105034593821 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

Plasminogen activator inhibitor 1 (PAI-1) is an inhibitor of fibrinolysis, thereby promoting blood clot stabilization. PAI-1 contributes to thrombosis, diet-induced obesity, and age-associated diseases, such as diabetes, cancer, and Alzheimer disease. Circulating PAI-1 level increases with age, contributing to the increased thrombotic risk in age-related diseases. In contrast, partial PAI-1 deficiency protects patients from cardiovascular morbidity and extends life span. Decreasing circulating PAI-1 levels has both experimental and therapeutic value. RNA gene therapy can regulate the levels of target proteins, including those not amenable to traditional small-molecule or antibody-based therapies. Here, we developed a therapeutic approach to induce long-lasting PAI-1 knockdown in vivo with small interfering RNA (siRNA)-lipid nanoparticles (siPAI-1). One dose of siPAI-1 resulted in 90% knockdown of plasma PAI-1 and lasted 10 days after administration with no overt toxicity. siPAI-1 decreased thrombus weight after complete ligation of the inferior vena cava (IVC) in young and aged mice and increased survival in aged mice 4 days post-IVC ligation. Hepatic PAI-1 mRNA expression in diet-induced obese mice was >10 times higher than in healthy mice and was exponentially correlated with body weight. One dose of siPAI-1 in obese mice resulted in 70% knockdown of circulating PAI-1. Furthermore, siPAI-1 normalized the supraphysiologic concentration of PAI-1 in aged mice and prolonged life span in a fast-aging mouse model. Thus, siRNA-mediated PAI-1 knockdown represents a long-term antithrombotic approach and effective strategy to limit pathologic impact of PAI-1 in aging and age-related diseases.

Author List

Ferraresso F, Skaer CW, Wei Z, Hur WS, Yu H, Seadler M, Chen THY, Dai W, Paul M, Lapointe C, Ketelboeter LM, Lund H, Rodriguez GG, Juang LJ, Strilchuk AW, Zhang Y, Cullis PR, Dyer MR, Gerras AL, Shi Q, Luyendyk JP, Flick MJ, Zheng Z, Kastrup CJ

Authors

Christian Kastrup PhD, MS Professor in the Surgery department at Medical College of Wisconsin
Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
Ze Zheng PhD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Disease Models, Animal
Gene Silencing
Humans
Longevity
Male
Mice
Mice, Inbred C57BL
Nanoparticles
Plasminogen Activator Inhibitor 1
RNA, Small Interfering
Thrombosis