Navigation Links
Friend or foe? How the body's clot-busting system speeds up atherosclerosis
Date:10/30/2008

Sometimes it's hard to tell friends from foes, biologically speaking. Naturally produced in the body, urokinase plasminogen activator and plasminogen interact to break up blood clots and recruit clean-up cells to clear away debris related to inflammation. In fact, urokinase manufactured as a drug effectively clears clogged arteries by generating clot-busting plasmin from blood-derived plasminogen.

However, despite the efficacy of urokinase and plasmin in clearing blood clots, evidence has shown that humans with a high baseline level of blood plasmin are at increased risk for heart attacks and for fast-developing forms of atherosclerosis. In addition, human arteries affected by atherosclerosis have an abundance of urokinase. These associations between plasmin, urokinase and increased atherosclerosis counter the notion that urokinase and plasmin protect against heart attacks by removing dangerous blood clots.

At first vascular biologists didn't know how to interpret these findings. Specifically, they wondered whether the high level of urokinase in atherosclerotic artery walls was contributing to atherosclerosis or was evidence of the body's efforts to fight it.

To try to resolve this puzzle, Dr. David A. Dichek, the John Locke Jr. Family Endowed Professor of Cardiology and associate director for research in the Division of Cardiology at the University of Washington (UW), and his team generated mice that were genetically engineered to produce more urokinase in their artery walls. These mice developed arteries with worse atherosclerosis, including thicker walls, narrower interiors, and limited blood flow. The mice died suddenly with clogged arteries and evidence of heart attacks.

Dichek noted other reasons why his team expected that increased activity of the urokinase/plasminogen system would promote atherosclerosis, including the roles of urokinase and plasminogen in inflammation and cell migration.

"However, despite much work," he said, citing other studies that seemed to predict a different outcome, "a coherent picture of the role of the urokinase/plasminogen system in the development of atherosclerosis has not yet emerged. We need to understand the molecular mechanisms that underlie clinically established relationships between urokinase production, activation of plasminogen, and the progression of atherosclerosis."

Discovering such molecular mechanisms might point to new ideas for treating or preventing atherosclerosis, which remains a leading cause of premature death from heart attacks, strokes, and aneurysms. In addition to his laboratory research on the molecular biology of atherosclerosis, Dichek is a general cardiologist at the UW Heart Center, where his clinical interests include heart disease prevention and chronic coronary artery disease treatment.

In recently published research, Dichek and his team bred transgenic mice that were deficient in Apolipoprotein E (and therefore had high cholesterol and triglyceride readings) and whose macrophagesthe blood cells that engulf and digest germs and other cellular debrisoverproduced urokinase. They also bred mice that didn't produce plasminogen because their genes for plasminogen were "knocked out."

"The transgenic and gene-knock out mice provided a useful experimental setting for investigating the mechanisms that explain the clinical correlations between urokinase-type plasminogen activator, plasminogen activation, and human vascular disease," the researchers wrote.

Their findings appear in the Oct. 29 Early Edition of the Proceedings of the National Academy of Sciences. The researchers found that the urokinase-type plasminogen activator produced by macrophages speeds up the growth of atherosclerotic plaques and promotes dilation of the root of the aorta, one of the heart's major blood vessels. The presence and activation of plasminogen were required for the biochemical pathways that converged to make already diseased blood vessels worse.

"These pathways appeared to affect [atherosclerotic] lesion progression rather than initiation," the authors noted, "and included actions that disproportionately increased lipid accumulation in the artery wall." The researchers found that, because these disease pathways depend on plasminogen, loss of plasminogen protected against atherosclerosis both with normal levels of urokinase and in the genetically engineered mice with increased urokinase.


'/>"/>

Contact: Leila Gray
206-685-0381
University of Washington
Source:Eurekalert

Related biology news :

1. When under attack, plants can signal microbial friends for help
2. Burnham researchers turn cancer friend into cancer foe
3. Beetles get by with a little help from their friends
4. MU scientists go green with gold, distribute environmentally friendly nanoparticles
5. Friendly bacteria protect against type 1 diabetes, Yale researchers find
6. Corporations can profit from being environmentally friendly
7. From foe to friend: Researchers use salmonella as a way to administer vaccines in the body
8. Baseball diamonds: the lefthanders best friend
9. Getting better with a little help from our micro friends
10. Over the back fence: gardeners get advice from neighbors, friends
11. Policing cells demand ID to tell friend from foe, say University of Pennsylvania cell engineers
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/22/2016)... Md. , June 22, 2016  The American College ... Trade Show Executive Magazine as one of the ... on May 25-27 at the Bellagio in Las ... on the highest percentage of growth in each of the ... of exhibiting companies and number of attendees. The 2015 ACMG ...
(Date:6/21/2016)... 2016 NuData Security announced today that Randy ... principal product architect and that Jon Cunningham ... development. Both will report directly to Christopher ... reflect NuData,s strategic growth in its product and ... demand and customer focus values. ...
(Date:6/15/2016)... 2016 Transparency Market Research ... Market by Application Market - Global Industry Analysis Size Share ... the report, the  global gesture recognition market  was ... is estimated to grow at a CAGR of ... Increasing application of gesture recognition technology ...
Breaking Biology News(10 mins):
(Date:12/2/2016)... ... December 01, 2016 , ... DrugDev believes the only way ... beautiful technology experience. All three tenets were on display at the 2nd Annual DrugDev ... over 40 sponsor, CRO and site organizations to discuss innovation and the future of ...
(Date:12/2/2016)... 2, 2016 The immunohistochemistry (IHC) market ... a CAGR of 7.3% during the forecast period of 2016 to ... laboratories segment accounted for the largest share of immunohistochemistry (IHC) market, ... , ... immunohistochemistry (IHC) market spread across 225 pages, profiling 10 companies and ...
(Date:11/30/2016)... 2016 /PRNewswire/ - Portage Biotech Inc. ("Portage" or "the ... excited to announce the formation of EyGen, Ltd. ... ophthalmology assets through proof of concept. EyGen,s lead ... Portage Pharmaceuticals Limited and being developed for topical ... anterior segment diseases. This agent has the potential ...
(Date:11/30/2016)... SAN DIEGO and BEIJING ... Ltd., a leading commercial provider of genomic services and ... expertise, announced today that it has completed a USD ... China Merchants Bank Co., Ltd.,s CMB International Capital Management ... SDIC Innovation Investment Management Co., Ltd. ("SDIC Innovation") and ...
Breaking Biology Technology: