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Dangerous plaques in blood vessels rupture by overproducing protein-busting enzymes
Date:3/29/2010

fats, and other debris. UW researchers learned that, inside some advanced plaques, macrophages churn out an overload of protein-digesting enzymes.

In a mouse study, Dickek and his team transplanted bone marrow containing macrophages that overproduce a protein-digesting enzyme known as urokinase into aged, atherosclerotic mice. These macrophages accumulated in some of the plaques. Compared to atherosclerotic mice of the same age, atherosclerotic mice with macrophages in overdrive had a much greater prevalence (61 percent versus 13 percent) of hemorrhage inside the plaques as well as more disruption of the fibrous caps covering the plaques.

"These same features hemorrhage and cap disruption are associated with ruptured plaques that cause heart attacks and strokes in humans," Dichek noted.

Urokinase was already known to be abundant in ruptured human plaques.

"But automatically blaming urokinase as the culprit without experimental evidence that it destabilized otherwise stable plaques would have been like seeing bright red trucks and firefighters at every flaming building and assuming they had set the blazes," Dichek said "In fact urokinase does have a protective effect at the right place and the right time, and we use it therapeutically as a clot-buster."

The researchers also observed that the increase in urokinase upped the activity of other protein-digesting enzymes that can eat away at the structural proteins that hold a plaque together. These other enzymes can weaken the framework of the plaque and also promote the self-destruction of nearby smooth muscle cells in the artery. These enzymes belong to a large family of remodeling enzymes called matrix metalloproteinases, or MMPs. The exact form of MMP implicated in this study hasn't been determined. Like urokinase, MMPs have helpful roles, depending on the location and circumstances in the body.

Urokinase also activates a substance in blood v
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Contact: Leila Gray
leilag@u.washington.edu
206-685-0381
University of Washington
Source:Eurekalert  

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