A missing enzyme conveys major heart protection in pre-clinical work

March 31, 2009

DURHAM, N.C. - Mice born without a certain enzyme can resist the normal effects of a heart attack and retain nearly normal function in the heart's ventricles and still-oxygenated heart tissue, according to a study by researchers at Duke University Medical Center.

The findings raise the possibility of a therapy that could stimulate the growth of blood vessels and limit damage from a heart attack as well as prevent an attack from occurring at all, the scientists said.

Normal mice that went through the same experiment had full heart attacks, suffering damage to their heart pumps and a lack of oxygen in their heart tissues, which are typical effects of a heart attack.

The scientists found that in mice lacking the enzyme GNSOR (or S-nitrosoglutathione reductase) the blood was able to get around the blockage point that normally would cut off blood to the heart because of remarkable capillary growth in these animals.

"There were blood vessels everywhere in these mice born without the enzyme," said Jonathan Stamler, M.D., a Duke professor of medicine and biochemistry and author of the study published in the Proceedings of the National Academy of Sciences online on March 27. "The hope is that this discovery someday could result in a therapy for new blood vessel growth that could be a sort of natural bypass in humans. Perhaps it could also benefit patients with peripheral artery disease, who cannot walk, for example, but who might be able to grow new blood vessels in their legs."

Stamler said his research group might look into the question of improving peripheral artery disease.

"Normally if you block the major artery to a heart, oxygen tension drops in the tissues - you can't get oxygen to the tissues and they die," Stamler said. "This appears to be a major step forward in the science of stimulating blood vessel growth around the heart, which many people have been trying to do."

"The remarkable aspect of this study is that we show that under conditions of elevated levels of nitric oxide, the heart can grow new blood vessels in the absence of chronic ischemia (inadequate circulation)," said Howard Rockman, M.D., Duke professor of medicine, chief of cardiology at Duke Heart Center and senior author of the study. Chronic ischemia usually occurs in people with severe coronary blockages, and who are at risk for heart attacks, he said.

"A therapy that can increase blood vessel growth in a person with only mild coronary artery narrowing would potentially decrease the amount of heart damage if a heart attack were ever to occur," Rockman said.

Stamler is an expert in nitric oxide (NO) chemistry and S-nitrosylation, a reaction perhaps as common in all cells as phosphorylation, a process that turns on enzymes for biological activity. Stamler's lab has been studying a class of compounds called S-nitrosothiols (SNOs) that regulate S-nitrosylation, and the most prevalent of these is GSNO (S-nitrosoglutathione). Rockman's group has been studying ways to protect the heart from failing, which has lead to a natural collaboration by these two investigators to study the role in S-nitrosylation in cardiac protection.

"We knew that NO had benefits in the heart and helped blood flow and blood vessel growth (angiogenesis), but we didn't know why, so that is what Dr. Rockman and I were exploring in this study," Stamler said.

The scientists also had discovered the enzyme in question, GSNOR, which breaks down GSNO and turns off the S-nitrosylation reactions in cells. Accumulating evidence suggests that the SNOs play various key roles in human health and disease.

"We wondered what the consequences would be if an animal did not have the GSNOR enzyme, so we created mice without the enzyme and studied heart function," Stamler said. "Lo and behold, there were clearly advantages to the animals, but there were no changes in their big blood vessels, no malformations. The answer was that small blood vessels - the capillaries - grew like crazy and established new pathways for blood flow." This was the case in six of the experimental animals studied compared with six normal mice.

Stamler said that the questions to ponder now are how long it takes to grow new blood vessels, and are there are dangerous or undesirable effects anywhere else in the animals?

Potentially, he foresees a day when people whose arteries are in the early stages of blockage could be treated so they can grow new blood vessels to preserve their heart function.

Duke University Medical Center

---

---

	Inflammatory Diseases of Blood Vessels by Gary S. Hoffman (Editor), Cornelia M. Weyand (Editor), Carol A. Langford (Editor), Jorg J. Goronzy (Editor) In recent years, considerable progress has been made in understanding the vasculitic diseases, largely due to the introduction of effective treatments for diseases that were once uniformly fatal, the conduct of structured clinical studies, and advances in immunology and molecular biology. Despite these achievements, the vasculitic diseases continue to be associated with morbidity and mortality from chronic organ damage, relapses, and the side effects of treatment. Investigations into the mechanisms of vascular inflammation may lead to a better comprehension of the pathogenesis of vasculitic diseases and to treatment that is more effective and less toxic. These areas of promising research, together with current knowledge about the vasculitic diseases, are extensively examined in this new...
	Human Anatomy and Physiology Practice Questions: Cardiovascular System: Blood Vessels and Blood Flow This is a collection of multiple choice questions on blood vessels and blood flow. Topics covered include blood vessels, blood flow, blood pressure, circulation, shock and circulation routes. These questions are suitable for students enrolled in Human Anatomy and Physiology I or II or General Anatomy and Physiology.
	Blood and Circulatory Disorders Sourcebook: Basic Consumer Health Information About Blood and circulatory System disorders, Such as Anemia, Leukemia, ... Thombophil (Health Reference Series) by Sandra J. Judd (Editor)
	The Fluid Mechanics of Large Blood Vessels (Cambridge Monographs on Mechanics) by T. J. Pedley (Author) The analysis of the circulation of the blood is one of the most important areas of fluid mechanics research, with far-reaching medical and physiological implications.
	Heart Talk: Understanding Cardiovascular Diseases : An Authoritative Source on the Prevention, Diagnosis and Treatment of Heart and Blood Vessel Dis by Mark V., Jr. Barrow (Author)
	Understanding Disease: How Your Heart, Lungs, Blood and Blood Vessels Function and Respond to Treatment by Glenn A. Langer (Author) Using real clinical cases as examples, Dr. G. A. Langer demystifies fifteen diseases of the cardiovascular and pulmonary systems. In clear, understandable language, he explains the nature of the illness, the body functions it affects, and the course of treatment indicated in each patient, providing invaluable understanding of how the human body works and how it responds to disease and to medical intervention. This information is deliberately intended to be as understandable, interesting and rewarding to the lay person as to medical professionals and students.
	Directions For The Dissection And Study Of The Cranial Nerves And Blood Vessels Of The Horse .. by Grant Sherman] [from old catal [Hopkins (Creator) This is a reproduction of a book published before 1923. This book may have occasional imperfections such as missing or blurred pages, poor pictures, errant marks, etc. that were either part of the original artifact, or were introduced by the scanning process. We believe this work is culturally important, and despite the imperfections, have elected to bring it back into print as part of our continuing commitment to the preservation of printed works worldwide. We appreciate your understanding of the imperfections in the preservation process, and hope you enjoy this valuable book.
	What Heart Patients Should Know And Do: Suggestions For Persons Suffering From Diseases Of The Heart And Blood Vessels (1913) by James Henry Honan (Author) Exercise, Diet, Prevention, Etc., And Advice As To The Regulations Of Their Lives.
	On gunshot injuries to the blood-vessels, founded on experience gained in France during the Great War, 1914-1918 by George Henry Makins (Author) This book is a replica, produced from digital images of the original. It was scanned at the University of Toronto Libraries and may contain defects, missing
	The heart and blood-vessels: their care and cure and the general management by Imanuel H Hirschfeld (Author) This book is a replica, produced from digital images of the original. It was scanned at the University of Toronto Libraries and may contain defects, missing pages or blemishes due to the original source content. The UT libraries have worked with various digital partners to provide the best possible customer experience and hope you enjoy the results.