Silencing of PAI-1 using siRNA-lipid nanoparticles reduces thrombosis and prolongs life span in murine models
Abstract
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.
Article Details
Authors (24)
Francesca Ferraresso
3Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
Chad W. Skaer
1Versiti Blood Research Institute, Milwaukee, WI
Zimu Wei
Woosuk S. Hur
2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
Hongyin Yu
1Versiti Blood Research Institute, Milwaukee, WI
Monica Seadler
1Versiti Blood Research Institute, Milwaukee, WI
Taylor H. Y. Chen
1Versiti Blood Research Institute, Milwaukee, WI
Wen Dai
Manoj Paul
1Versiti Blood Research Institute, Milwaukee, WI
Catherine Lapointe
5Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC
Laura M. Ketelboeter
1Versiti Blood Research Institute, Milwaukee, WI
Hayley Lund
1Versiti Blood Research Institute, Milwaukee, WI
Geoffrey G. Rodriguez
1Versiti Blood Research Institute, Milwaukee, WI
Lih Jiin Juang
2Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, Canada
Amy W. Strilchuk
2Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, Canada
Youjie Zhang
1Versiti Blood Research Institute, Milwaukee, WI
Pieter R. Cullis
Mitchell R. Dyer
1Versiti Blood Research Institute, Milwaukee, WI
Allison L. Gerras
4Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI
Qizhen Shi
Versiti Blood Research Institute, Milwaukee, WI
James P. Luyendyk
Michigan State University, East Lansing, Michigan, United States
Matthew J. Flick
2Department of Pathology and Laboratory Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Ze Zheng
State Key Laboratory of Photonics and Communications, Center for Quantum Sensing and Information Processing, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University 1 , Shanghai 200240,
Christian J. Kastrup
Versiti Blood Research Institute, Milwaukee, Wisconsin, United States