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Methods for Increasing Plasmin Activity and Promoting Plaque Regression in the Treatment of Atherosclerosis

The vasa vasorum are a network of microvasculature that originate primarily in the adventitia of large arteries. Neovascularized second order vasa vasorum are associated with more advanced stages of human atherosclerosis. Proteases that degrade the extracellular matrix (ECM)/basement membrane (BM) play a key role in matrix remodeling during normal wound healing as well as in vascular diseases such as atherosclerosis. Plasmin contributes to matrix remodeling through its own proteolytic activity and by activating numerous matrix metalloproteinases (MMPs). Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of plasmin production.

Dartmouth scientists have now found that a potent anti-angiogenic protein, rPAI-123, causes regression/collapse of adventitial vasa vasorum in atherogenic female LDLR-/-ApoB-48-deficient mice by stimulating an increase in plasmin activity. The increased plasmin activity, accompanied by elevated MMP-3 activity, degrades major ECM/BM components that provide support to expanding vasa vasorum. Biochemical studies demonstrate that rPAI-123 enhances plasmin activity through a novel mechanism where rPAI-123 and PAI-1 bind plasminogen in a cooperative fashion to regulate plasmin activity. The effects of simultaneously combining various concentrations of rPAI-123 and PAI-1 with plasminogen and tPA favors plasmin production when rPAI-123 is at the highest concentrations. Therefore, rPAI-123 is of use in increasing plasmin activity, inhibiting angiogenic vasa vasorum, promoting plaque regression and treating atherosclerosis.

These findings are claimed in the published PCT application No. PCT/US2012/023714. We are seeking an industrial partner to further refine and market this technology. (Ref: #J618)

Last Updated: 2/4/13