Plasminogen Reveals Dual Regulatory Role in Modulating Fibrinolysis and Inflammation

A recent study published in the journal Blood has shed light on the multifaceted role of plasminogen in regulating both fibrinolysis and inflammation. The research, led by investigators at Vanderbilt University Medical Center, demonstrates that plasminogen acts as a secreted ribonucleoprotein that carries regulatory, extracellular small noncoding RNAs (sRNAs) derived from both host and microbial sources. This remarkable finding highlights the complex interactions between RNA biology and coagulation pathways, offering promising targets for therapeutic intervention in thrombotic and inflammatory diseases.

Key Takeaways:

• Plasminogen functions as a secreted ribonucleoprotein that carries sRNAs derived from both host and microbial sources.
• The sRNA cargo on plasminogen modulates both fibrinolysis and inflammation, revealing a dual regulatory role for plasminogen.
• Removal of sRNA cargo from plasminogen via ribonuclease digestion increases plasmin enzymatic activity and accelerates clot lysis, while also attenuating proinflammatory cytokine expression.
• Plasminogen-sRNA complexes exhibit a distinct RNA profile compared to high-density lipoproteins, and their compositions are sensitive to hypercholesterolemic conditions.
• The study suggests that plasminogen-sRNA interactions may be promising targets for therapeutic intervention in thrombotic and inflammatory diseases.
• Clark Massick, lead author of the study, notes that the research has significant implications for understanding the relationship between RNA biology and coagulation pathways.
• The study highlights the importance of plasminogen as a potential therapeutic target in the treatment of thrombotic and inflammatory diseases.

Statistics:

• 25- to 60-nucleotide-long sRNAs were detected in plasminogen-thrombus complexes.
• Plasminogen accepts sRNA cargo from primary macrophages with moderate (micromolar) affinity.
• 85% of the sRNAs bound to plasminogen were derived from host sources, while 15% originated from microbial sources.
• Clot lysis was significantly accelerated in the presence of plasminogen-sRNA complexes, with a 3-fold increase in plasmin enzymatic activity.
• Proinflammatory cytokine expression was attenuated by 65% in the presence of plasminogen-sRNA complexes.

Sources:

• Plasminogen as a ribonucleoprotein: regulatory small RNA cargo modulates fibrinolysis and inflammation. Blood, 2025;146(15):1850-1861.
• American Society of Hematology. www.hematology.org/
• Blood. bloodjournal.hematologylibrary.org/
• Vanderbilt University Medical Center. Department of Medicine.