Friend or foe? How the body's clot-busting system speeds up atherosclerosis

October 31, 2008

Resolving this paradox may lead to new ideas for preventing or treating artery disease

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 macrophages-the blood cells that engulf and digest germs and other cellular debris-overproduced 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.

University of Washington

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	Plasminogen-Related Growth Factors - No. 212 by John Wiley & Sons
	Tissue Plasminogen Activator in Thrombolytic Therapy by Burton E. Sobel (Author), Desire Collen (Author), Elliott B. Grossbard (Editor) The book proceeds through a review of the biology, clinical pharmacology, and pharmacokinetics of tissue plasminogen activator with special attention to rt-PA, followed by a review of the clinical experience accumulated over the last 2 1/2 years in myocardial infarction, pulmonary embolism, venous thrombosis, and peripheral arterial occlusion.
	Plasminogen: Structure, Activation and Regulation by David Morton Waisman (Author) This volume showcases the most important developments in the area of plasminogen regulation. The book is composed of about 16 chapters dealing with a range of topics including the mechanisms of activation of plasminogen, the structure of plasminogen and plasminogen activators, the role of plasminogen in various physiological and pathological processes (such as tumor growth and progression, wound healing and fibrinolysis) and the interrelationship of the plasmin/MMP proteolytic systems.
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	Plasminogen: Webster's Timeline History, 1955 - 2001 by Icon Group International (Author) Webster's bibliographic and event-based timelines are comprehensive in scope, covering virtually all topics, geographic locations and people. They do so from a linguistic point of view, and in the case of this book, the focus is on "Plasminogen," including when used in literature (e.g. all authors that might have Plasminogen in their name). As such, this book represents the largest compilation of timeline events associated with Plasminogen when it is used in proper noun form. Webster's timelines cover bibliographic citations, patented inventions, as well as non-conventional and alternative meanings which capture ambiguities in usage. These furthermore cover all parts of speech (possessive, institutional usage, geographic usage) and contexts, including pop culture, the arts, social...
	Plasminogen: Webster's Timeline History, 2002 - 2007 by Icon Group International (Author) Webster's bibliographic and event-based timelines are comprehensive in scope, covering virtually all topics, geographic locations and people. They do so from a linguistic point of view, and in the case of this book, the focus is on "Plasminogen," including when used in literature (e.g. all authors that might have Plasminogen in their name). As such, this book represents the largest compilation of timeline events associated with Plasminogen when it is used in proper noun form. Webster's timelines cover bibliographic citations, patented inventions, as well as non-conventional and alternative meanings which capture ambiguities in usage. These furthermore cover all parts of speech (possessive, institutional usage, geographic usage) and contexts, including pop culture, the arts, social...
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