Friend or foe? How the body's clot-busting system speeds up atherosclerosisOctober 31, 2008Resolving 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 Science News and Science Current Events Tag Cloud This tag cloud is a visual representation of term frequencies of random science news topics with common terms grouped together and emphasized by their display size. Memory loss Antarctic Ubiquitin Spinal Muscular Atrophy Telomeres Shark Attack Robotics Mammography Soybean Coronary Heart Disease Postpartum Depression Contact Lenses Thyroid Cancer Sleep Disorder Bad Breath Biomolecules Vitamin D Deficiency Bison Acetylcholine Zebrafish Atmosphere Anemia Miscarriage Cancer Survivors Obstructive Sleep Apnea
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Related Plasminogen Current Events and Plasminogen News Articles Stanford study expands window for effective stroke treatment Once symptoms start, there's only a tiny window of time for stroke victims to get life-saving treatment. Now, research from the Stanford University School of Medicine has cracked that window open a bit wider. UT Houston researchers use stroke patient's own stem cells in trial for first time Phase I trial will enroll 10 patients For the first time in the United States, a stroke patient has been intravenously injected with his own bone marrow stem cells as part of a research trial at The University of Texas Medical School at Houston. Patients who wake up with stroke may be candidates for clot-busters Giving clot-busting drugs to patients who wake up with stroke symptoms appears to be as safe as giving it to those in the recommended three-hour window, according to researchers at The University of Texas Medical School at Houston. Plasminogen activator inhibitor type-1 -- a potential link between heart failure and diabetes Researchers at the University of Vermont Cardiovascular Research Institute, Colchester, Vermont have found that increased expression in the heart of plasminogen activator inhibitor type-1 (PAI-1) is profibrotic. Stroke therapy window might be extended past nine hours for some Some patients who suffer a stroke as a result of a blockage in an artery in the brain may benefit from a clot-busting drug nine or more hours after the onset of symptoms. The findings are published in the online edition of Radiology. Blocking toxic effects could make clot-buster safer Since the introduction of the life-saving clot-busting drug tPA more than a decade ago, evidence has been accumulating that tPA (tissue-type plasminogen activator) can be a double-edged sword for a brain affected by stroke. Apolipoprotein(a): A natural regulator of inflammation In a study to be published in the January 09 issue of Experimental Biology and Medicine, Hoover-Plow and co-workers in seeking to define a role of apo(a) in leukocyte recruitment have identified a novel activity of apo(a) apolipoprotein that may function as a natural and cell specific suppressor of the inflammatory response in vivo. Ultrasound waves aid in rapid treatment of DVT The use of ultrasound waves for deep vein thrombosis (DVT) may help dissolve blood clots in less time than using clot-busting drugs alone, according to researchers at Emory University. Mouse studies suggest daily dose of ginkgo may prevent brain cell damage after a stroke Working with genetically engineered mice, researchers at Johns Hopkins have shown that daily doses of a standardized extract from the leaves of the ginkgo tree can prevent or reduce brain damage after an induced stroke. Protein complementarity may offer new insights into autoimmune diseases The discovery of "complementary" antibodies against plasminogen in patients with blood vessel inflammation caused by anti-neutrophil cytoplasmic autoantibodies (ANCAs) may lead to new approaches to research, testing, and treatment of ANCA vasculitis and other autoimmune diseases, suggests a paper in the December Journal of the American Society of Nephrology (JASN). More Plasminogen Current Events and Plasminogen News Articles |
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