Mini heart attacks lessen damage from major ones

December 02, 2008

New class of lipids suggests new treatment approach for heart attacks

Researchers have discovered one potential mechanism by which briefly cutting off, then restoring, blood flow to arteries prior to a heart attack lessens the damage caused, according to a study published today in the journal Cardiovascular Research. The new mechanism points to how future drugs could provide protection ahead of heart attacks and strokes for those at highest risk. In the nearer term, the work may help to prevent damage caused as U.S. heart surgeons temporarily cut off blood flow 450,000 times each year to perform coronary artery bypass graft surgeries. Lastly, the discoveries hold clues to the value of the Mediterranean diet beyond red wine.

In severely diseased coronary arteries, fatty deposits in blood vessel walls become more likely to rupture, which releases proteins into the blood that cause blood clots and cut off blood flow. When a vessel becomes completely blocked (ischemia) the downstream tissue begins to die for lack of oxygen and nutrients. Worse yet, when blood flow is restored (reperfusion), the returning blood throws off cellular chemistry, creating as a side-product a burst of highly reactive "free radicals" that tear apart cell components and cause cells to self-destruct. Later in the process, the immune system attacks the cardiac tissue damaged by ischemia and reperfusion, causing inflammation which can lead to heart failure.

In 1986 then medical student Chuck Murry at Duke University first described a technique called ischemic preconditioning (IPC), which quickly cuts off then restores blood flow to the heart. He found that IPC somehow protected heart tissue against the damage caused by subsequent, prolonged blood vessel blockages. An emerging theory holds that this natural early warning system of IPC has evolved to protect against heart attack. Labs worldwide are seeking to re-create or strengthen this natural protection against ischemia/reperfusion (IR) injury. In the current study, researchers for the first time determined that IPC caused more of a key molecule, nitro-linoleic acid (LNO2), to be made in ischemic cells.

"LNO2 appears to be important in the mechanism by which IPC triggers the body's natural defense mechanisms against heart attack before the major attack comes," said Paul S. Brookes, Ph.D., associate professor of Anesthesiology and of Pharmacology and Physiology at the University of Rochester Medical Center. "Obviously, this natural response, when it follows a major heart attack, is often too little too late. Our hope is that boosting the effect in patients at high risk, perhaps by administering LNO2 beforehand, will reduce heart attack damage in the future. Even sooner, we may be able dramatically reduce reperfusion injury suffered in surgical settings."

Study Details

Going into the study, the mechanisms underlying IPC protection were controversial, but a consensus had emerged recently that mitochondria were involved. The cell's powerhouse, mitochondria use oxygen to convert nutrients into cellular energy supply.

As they do so, they create a gradient of protons across their membranes. When the gradient becomes too large, it triggers the mitochondria to use oxygen to generate free radicals. The problem gets much worse when blood returns to a vessel after a blockage, bringing with it a surge of oxygen and nutrients.

It has long been thought that a group of proteins in the mitochondrial membrane act as a "safety valve" by dissipating too large proton gradients when necessary, which slows free radical generation. The current study identified a novel mechanism involving LNO2, by which IPC turns on this safety valve.

Given their results, the authors propose the following protective mechanism: temporary ischemia causes the generation of nitrated lipids inside the mitochondria via currently unknown mechanisms involving metabolites of the gas nitric oxide (NO). These lipids, including LNO2, then become attached to two proteins - adenine nucleotide translocase and uncoupling protein 2 - changing their shape such that they allow a proton leak across the mitochondrial membrane. The leak lowers the proton gradient just enough to lessen free radical production.

While the current study only looked at the immediate effects of LNO2 treatment, the literature suggests that LNO2 also limits the misplaced immune response seen after reperfusion, suggesting a dual treatment effect. Past studies found that LNO2 inhibits Nfkappa B, a protein known to switch on genes that drive inflammation. LNO2 also activates peroxisome proliferator activated receptor gamma and heme oxygenase 1, both of which block inflammation.

The major finding of the study is that LNO2 is formed naturally in mitochondria during IPC in an isolated rat heart, and that adding extra LNO2 protects heart muscle cells from IR injury. The team measured the ability of isolated rat heart cells to survive ischemia using a dye that the live cells keep out, but that dead cells take in. That enabled researchers to count how many cells survived with and without LNO2 added.

In normal cells following ischemia 70 percent died, but for those receiving extra LNO2 (0.5 micromolar), only 30 percent died. The amount of the LNO2 added was not much more than naturally occurs, suggesting its effect is "extremely potent," researchers said. The LNO2-related proton leak also occurs at the protein level within seconds, a vital quality of any future therapy, considering that IR injury greatly increases with each second it is allowed to proceed.

Brookes is part of the Mitochondrial Research & Innovation Group (MRIG) at the Medical Center, which last year reported in the Journal of Molecular and Cellular Cardiology on the design and testing of a series of patented nitric oxide donors that break down and release NO only within the mitochondria, and protect the heart from ischemia. The team believes these NO donors may work in part by increasing LNO2 supply. In the acute setting, such drugs may offer an advantage over standard nitric oxide donors like nitroglycerin, which increase blood flow in diseased arteries by causing them to dilate throughout the body. Standard NO donors also depress cardiac function by decreasing the pressure of blood returning from the body back into the heart. Early tests in a mouse model have confirmed that the new MRIG NO donor drugs are cardioprotective in-vivo, and do not cause system-wide vessel dilation side effects.

Bruce Freeman, Ph.D., chair of the Department of Pharmacology & Chemical Biology at the University of Pittsburgh School of Medicine, also led the study. Other contributors included postdoctoral fellow Sergiy Nadtochiy, Ph.D. in Rochester, and Paul Baker, Ph.D. research assistant professor in Pittsburgh.

"Our interest in this area stems from the fact that many different stimuli appear to funnel down into the mitochondria where they may trigger LNO2 production, any of which may suggest a new way to prevent damage," Freeman said. "Along with IPC, olive oil has been shown to produce LNO2 in the stomach, offering an explanation for the value of the Mediterranean diet."

University of Rochester Medical Center

Minding My Mitochondria 2nd Edition: How I overcame secondary progressive multiple sclerosis (MS) and got out of my wheelchair.
by Terry L. Wahls (Author), Tom Nelson (Illustrator)

Dr. Terry Wahls links micronutrient starvation to the epidemics of chronic disease that are overtaking modern society. She explains the key roles mitochondria play in maintaining a healthy brain and body. Americans are eating so poorly, something we all know to be true, that the majority of Americans are missing key building blocks that are needed for brain cells to be healthy. The result is an epidemic of depression, aggression, multiple sclerosis and early dementia. She then teaches you how to eat for healthy mitochondria, a healthy brain and a healthy body in language that is clear and concise, even for those without a science background. In this book, Dr. Wahls explains basic brain biology in simple terms. She tells us what vitamin, mineral and essential fat building blocks are...

Mitochondria (Scheffler, Mitochondria)
by Immo E. Scheffler (Author)

"This volume inspires. It certainly will be much appreciated by cell biologists all over the world."
Quarterly Review of Biology, March 2009This book is the eagerly awaited second edition of the best-selling Mitochondria, a book widely acknowledged as the first modern, truly comprehensive authored work on the important, scientifically fundamental topic of the cellular organelles known as mitochondria.This new edition brings readers completely up to date on the many significant findings that have occurred in the eight years since the book was first published. As in that seminal first edition, the second edition tackles the biochemistry, genetics, and pathology of mitochondria in different organisms. The new edition provides thorough updates of all literature concerning this vital...

Mitochondria: The Dynamic Organelle (Advances in Biochemistry in Health and Disease)
by Stephen W. Schaffer (Editor), M. Saadeh Suleiman (Editor)

This book is indispensable to researchers in fields as diverse as Molecular Biology and Biophysics. It covers the important role that mitochondria play in a variety of biochemical spheres. It analyses how mitochondria affect metabolic pathways, how they are active in the regulation of cytosolic constituents, and their role in initiating signal pathways. Also covered are the way mitochondria help to regulate apoptosis, and how they modulate cellular hypertrophy and proliferation. It gives an overview of the emergence of mitochondria as an important regulator of cell signaling, with a particular focus on their pathophysiology.

Mitochondria: Practical Protocols (Methods in Molecular Biology)
by Dario Leister (Editor), Johannes Herrmann (Editor)

This book offers a broad collection of methods for studying the molecular biology, function, and features of mitochondria. In the past decade, mitochondrial research has elucidated the important influence of mitochondrial processes on integral cell processes. This practical guide presents a wide spectrum of mitochondrial methods, each written by specialists with solid experience and intended for implementation by novice and expert researchers alike.

Mitochondria: Structure, Functions and Dysfunctions (Cell Biology Research Progress)
by Oliver L. Svensson (Editor)

In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. Mitochondria are often described as 'cellular power plants' because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of the chemical energy. In addition to supplying cellular energy, mitochondria are involved in a range of other processes, such as signalling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. This book reviews research on the mitochondrial metabolism in age-related neurodegenerative disorders such as Alzheimer's and Parkinson's disease; mitochondria and ageing; apoptosis and peritoneal injury; and, diabetes, mitochondria and brain endothelium dysfunction as a dangerous triad for...

Living Well With Mitochondrial Disease: A Handbook for Patients, Parents, and Families
by Cristy Balcells (Author)

LIVING WELL WITH MITOCHONDRIAL DISEASE helps make sense of mitochondrial disease (Mito), an overwhelming and complex group of diagnoses that has grown exponentially in recent years. The most common of all metabolic disorders, thought to be more common than cystic fibrosis and broader-reaching than most genetic diseases, Mito can affect babies, children, and teens from birth or at any point during their development. Previously healthy adults, as well as adults with a history of unexplained fatigue, are increasingly receiving a Mito diagnosis. Some children with autism spectrum disorders who have medical issues such as digestive difficulties and fatigue are also being identified as having a mitochondrial disorder. This guide is the first book about Mito written for patients and their...

Acquired Mitochondropathy - A New Paradigm in Western Medicine explaining Chronic Diseases: The Safety Guide for Prevention and Therapy of Chronic Ailments
by Enno Freye (Author)

The book on Acquired Mitochondropathy offers a new perspective on the understanding and the treatment of chronic ailments. Addressing a new paradigm deemed necessary, since in one of every four adults in the western world chronic ailments are on the rise. Resulting from energy dysfunction of cellular organelles, the mitochondria, the most of the common symptoms the physician faces during medical consultation are presented. An increasing focus on chronic disabilities presents difficulties for the busy practitioner, since patients typically describe a complex pattern of discomfort, disability, and distress, with pain affecting physical, social, and psychological functioning, which have to be put in the proper perspective. Since clinicians must efficiently condense widely varied...

Life Ascending: The Ten Great Inventions of Evolution
by Nick Lane (Author)

“Original and awe-inspiring . . . an exhilarating tour of some of the most profound and important ideas in biology.”—New Scientist Where does DNA come from? What is consciousness? How did the eye evolve? Drawing on a treasure trove of new scientific knowledge, Nick Lane expertly reconstructs evolution’s history by describing its ten greatest inventions—from sex and warmth to death—resulting in a stunning account of nature’s ingenuity. 20 figures

Mitochondria and Cancer
by Keshav Singh (Editor), Leslie Costello (Editor)

The book begins with a general overview of Warburg Hypothesis, mitochondrial structure and function, and then outline more specifically the metabolic and molecular alterations in mitochondria that are associated with human cancer and their clinical implications. An emphasis is also placed on mtDNA mutations and their potential role in carcinogenesis. The potential use of mitochondria as biomarkers for early detection of cancer, or as unique cellular targets for novel and selective anti-cancer agents will also be discussed.