Chymase Inhibition Resolves and Prevents Deep Vein Thrombosis Without Increasing Bleeding Time in the Mouse Model

Area of Science:

• Cardiovascular Research
• Hematology
• Immunology

Background:

• Deep vein thrombosis (DVT) is a significant cardiovascular disease and a leading cause of pulmonary embolism.
• Current anticoagulants for DVT carry bleeding risks, necessitating novel therapeutic strategies.
• Mast cells have been implicated in DVT, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the role of mast cell-derived mouse mast cell protease-4 (mMCP-4) in DVT pathogenesis.
• To evaluate the therapeutic potential of inhibiting mMCP-4 in DVT models.

Main Methods:

• Utilized two mouse models of DVT: partial ligation and ferric chloride-induced inferior vena cava injury.
• Employed genetic depletion (mMCP-4 knockout) and pharmacological inhibition (TY-51469) of mMCP-4.
• Assessed thrombus formation, blood flow, bleeding times, and enzymatic activity of mMCP-4 and plasmin.

Main Results:

• Genetic or pharmacological inhibition of mMCP-4 significantly resolved and prevented venous thrombus formation in DVT models.
• mMCP-4 inhibition did not affect bleeding times in healthy or DVT mice.
• Endogenous chymase, including mMCP-4, was found to limit plasmin activity within thrombi.

Conclusions:

• Mouse mast cell protease-4 (mMCP-4) plays a critical role in DVT development.
• Inhibiting chymase activity presents a novel strategy for DVT treatment, resolving or preventing thrombosis without impacting coagulation.
• Mast cell-containing chymase is present in human DVT, suggesting translational relevance.