Silencing of PAI-1 using siRNA-lipid nanoparticles reduces thrombosis and prolongs life span in murine models.

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.