Regulation Of Vascular Tone By Indoleamine 2,3-dioxygenase
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
As part of their normal function, blood vessels dilate and contract, for example in response to the pulsative force with which our heart pumps the blood around the circulation. Blood vessels produce several different chemicals that cause vessel relaxation, and these vary depending on several factors, such as the blood vessel involved, its diameter and precise location within our body. In addition to responding to the pulsative nature of blood flow, blood vessels also respond to many other condit ....As part of their normal function, blood vessels dilate and contract, for example in response to the pulsative force with which our heart pumps the blood around the circulation. Blood vessels produce several different chemicals that cause vessel relaxation, and these vary depending on several factors, such as the blood vessel involved, its diameter and precise location within our body. In addition to responding to the pulsative nature of blood flow, blood vessels also respond to many other conditions, including certain diseases, so that it is not surprising that many of the commonly used cardiovascular drugs target to change blood vessel tone, either increasing or decreasing blood pressure, depending on the circumstances involved. The present application is based on the discovery, in the mouse, that during a systemic infection a specific protein is induced in the cells that line blood vessels. This protein degrades a certain amino acid into a novel chemical, called kynurenine. We observed that kynurenine has previously unrecognised vessel-relaxing properties. The present project will investigate the importance of kynurenine formation as a novel pathway in the regulation of vascular tone. Mice, in which the activity of the kynurenine-producing protein will be modulated (both up and down) will be used in conjunction with blood pressure and other relevant measurements. In addition, the role of a unique molecule, called superoxide anion radical, in the production of kynurenine by the protein will also be tested. If our results confirm that the protein and kynurenine are indeed involved in regulating vascular tone, our research could have tremendous impact on many aspects of normal physiology as well as cardiovascular diseases that remain the major single cause of death in Australia.Read moreRead less
Role Of Endothelial Vasodilator Mechanisms In Cardiovascular Control During Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$225,500.00
Summary
Cardiovascular diseases such as stroke and heart attack are the greatest killers in developed societies such as Australia. We now know that a number of metabolic disorders, and genetic and lifestyle factors, can increase the likelihood of individuals developing cardiovascular disease later in life, such as obesity, diabetes, and smoking. In many cases, individuals with these risk factors also have high blood pressure, which is a known cause of stroke and heart attack. This seems to be a particul ....Cardiovascular diseases such as stroke and heart attack are the greatest killers in developed societies such as Australia. We now know that a number of metabolic disorders, and genetic and lifestyle factors, can increase the likelihood of individuals developing cardiovascular disease later in life, such as obesity, diabetes, and smoking. In many cases, individuals with these risk factors also have high blood pressure, which is a known cause of stroke and heart attack. This seems to be a particular problem in patients with diabetes, a condition that currently affects around 150 million people worldwide. Indeed, almost 70% of patients that develop diabetes in later life, also develop high blood pressure. The aim of the studies outlined in this application is to increase our understanding of the way diabetes affects blood pressure. High blood pressure often accompanies established diabetes, but we have recent evidence that suggests that a gas (nitric oxide) made by the cells that line blood vessels (endothelial cells) and in nerve cells, protects the cardiovascular system from hypertension during the onset of diabetes. Our experiments will show whether the 'protective' nitric oxide comes from nerves or the endothelial cells, and how it affects various blood pressure control mechanisms in diabetes. Our experiments will also show whether this protective action of nitric oxide is eventually lost as the organ damage that occurs in diabetes proceeds. This information should help in the design of new drug treatments and other therapies aimed at reducing the occurrence of high blood pressure, and hence cardiovascular disease, in diabetes.Read moreRead less
Does Inhibition Of Myeloperoxidase Attenuate Atherosclerosis?
Funder
National Health and Medical Research Council
Funding Amount
$572,659.00
Summary
This project examines whether inhibition of a protein that produces bleach and is part of the immune system inhibits the stiffening of arteries, i.e. the major cause of cardiovascular disease that leads to heart attack and stroke. The project uses a pharmacological approach, employing a new class of chemical compounds. If successful, the project will contribute to the establishing of a novel therapeutic target to combat cardiovascular disease.
We have found that during infection a protein (called IDO) is made in cells lining arteries. IDO degrades tryptophan into kynurenine, which can open arteries, while blocking IDO increases blood pressure. We will now study the importance of this metabolic pathway in various diseases using mice with either absent or high levels of IDO, and also perform the first such studies in human blood vessels. We predict the research to have a tremendous impact on our understanding of cardiovascular diseases.
Myoendothelial Gap Junctions: Their Composition And Role In Vasodilator Responses Attributed To EDHF
Funder
National Health and Medical Research Council
Funding Amount
$282,750.00
Summary
Cardiovascular disease, including coronary heart disease and stroke, continues to be the major cause of death in Australia and hypertension is a significant risk factor. The endothelium, which lines blood vessels of all sizes, is critical to the control of blood flow to the organs of the body. Endothelial cells release factors which can cause blood vessels to constrict or to relax, thus decreasing or increasing blood flow, respectively. Under normal conditions, the endothelium is more important ....Cardiovascular disease, including coronary heart disease and stroke, continues to be the major cause of death in Australia and hypertension is a significant risk factor. The endothelium, which lines blood vessels of all sizes, is critical to the control of blood flow to the organs of the body. Endothelial cells release factors which can cause blood vessels to constrict or to relax, thus decreasing or increasing blood flow, respectively. Under normal conditions, the endothelium is more important as a source of relaxing factors, while under hypertensive conditions, the balance is shifted in favour of the release of constricting factors. Thus, restoration of the vasodilatory function of the endothelium is seen as an important new therapeutic target in the treatment of vascular disorders. Present data suggests that the action of one of the major endothelial derived vasodilatory factors, the so-called endothelium-derived hyperpolarizing factor, EDHF, requires the presence of particular structures within the vascular wall, but little is known about the molecules of which they are comprised. We have identified two unique situations, during development and during hypertension, when these structures are present in vessels in which they are absent in normal adults. We will use gene microarrays to identify the specific molecules involved in these structures and use physiological studies to test the role of these proteins and structures in vasodilatory responses. The results of these studies may identify new targets for therapeutic intervention to restore the action of EDHF in hypertension.Read moreRead less