Anti-atherosclerotic Effects Of Angiotensin Fragments & Non-AT1 Receptors: Validation As Innovative Therapeutic Targets
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the horm ....In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the hormone, angiotensin II. Angiotensin II has been found to trigger many factors that cause thickening of the vessel wall, inflammation and imbalances in vasodilator capacity (e.g. oxidative stress and endothelial dysfunction), all of which contribute to atherosclerosis. Clinical trials with drugs that inhibit the formation of angiotensin II (ACE inhibitors), or block the action of angiotensin II (angiotensin receptor antagonists), have demonstrated a significant decrease in mortality in patients with high risk for cardiovascular disease. However their mechanism(s) of action are not fully understood as the circulating levels of shorter fragments of angiotensin II (such as Ang IV and Ang (1-7)) are raised in the blood when these drugs are used and may contribute to the protective effects of these drugs. Importantly, we have found that both Ang IV and Ang (1-7) have protective effects in atherosclerotic blood vessels. Therefore, we hypothesise that fragments of angiotensin II (such as Ang IV and others) exert anti-atherogenic effects via distinct binding sites that oppose the effects caused by angiotensin II, and that these may be partly responsible for the cardio-protective effects of the ACE inhibitors and angiotensin receptor antagonists. Thus, information gained in our study will be useful in directing future prescription practices in clinical management of CHD and stroke, and for designing new therapeutic compounds for the management of atherosclerosis.Read moreRead less
Manipulation Of Intracellular Arginine Content In Endothelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$476,264.00
Summary
The lining layer of blood vessels (termed the 'endothelium') plays a vital role in the control of blood vessel function. Recently it has been shown that risk factors for heart and vascular disease (smoking, high blood pressure, high cholesterol and diabetes), heart attack and heart failure are associated with an abnormally functioning endothelium. In particular, the endothelium maintains blood vessels in a relaxed state, prevents the formation of blood clots (which may cause heart attack and str ....The lining layer of blood vessels (termed the 'endothelium') plays a vital role in the control of blood vessel function. Recently it has been shown that risk factors for heart and vascular disease (smoking, high blood pressure, high cholesterol and diabetes), heart attack and heart failure are associated with an abnormally functioning endothelium. In particular, the endothelium maintains blood vessels in a relaxed state, prevents the formation of blood clots (which may cause heart attack and stroke) and prevents the thickening of blood vessels. These important actions of the endothelium are explained by the production of nitric oxide (NO) a small chemical messenger that is derived from an amino acid, L-arginine, which circulates in blood. The amount of NO produced by endothelial cells is very dependent on the amount of arginine available, and this is determined by a careful balance between the amount of arginine taken (transported) into cells and the amount that is destroyed (metabolized) by an enzyme called arginase. Research undertaken in our laboratory is directed at understanding the important balance between arginine transport and arginase activity, as a basis for identifying new ways to prevent and treat cardiovascular disease. The current proposal describes a series of studies which will critically examine the importance of arginine transport and arginase activity, using transgenic models of over-activity and under-activity of these systems. Once established we will test the possibility that manipulating these systems may prevent atherosclerosis.Read moreRead less
Is NADPH Oxidase The Trigger For Accelerated Atherosclerosis Caused By Bacteria?
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
Cardiovascular disease is the leading cause of death and morbidity world-wide. However, its incidence is not fully explained by the presence of conventional risk factors, such as high cholesterol, hypertension, diabetes and cigarette smoking. Steadily growing evidence indicates that bacterial infection, particularly by Chlamydia pneumoniae and Helicobacter pylori, is also strongly linked to atherosclerotic lesion formation and increased risk of a cardiovascular event. This project will investiga ....Cardiovascular disease is the leading cause of death and morbidity world-wide. However, its incidence is not fully explained by the presence of conventional risk factors, such as high cholesterol, hypertension, diabetes and cigarette smoking. Steadily growing evidence indicates that bacterial infection, particularly by Chlamydia pneumoniae and Helicobacter pylori, is also strongly linked to atherosclerotic lesion formation and increased risk of a cardiovascular event. This project will investigate a new aspect to the body s defence against bacterial infection which involves production of oxygen radicals by the blood vessel wall. We propose that although this response of the artery to bacteria in the blood is beneficial in the short term, it inadverently initiates a chronic inflammatory process that ultimately accelerates development of artery disease. If this is the case, the oxygen radical production by the enzyme, NADPH oxidase, in the artery wall may represent the missing link between bacterial infection and atherosclerosis. We will therefore firstly test whether two bacteria, Chlamydia pneumoniae and Helicobacter pylori, can acutely induce artery inflammation in this way. We will then perform definitive studies to test whether mice infected with these bacteria develop accelerated atherosclerosis, and if so, whether this effect is dependent on NADPH oxidase activity in the artery wall. Finally, we will test the efficacy and importance of timing of antibiotic therapy to prevent atherosclerotic lesion formation.Read moreRead less
Development Of A Protein Tyrosine Kinase Inhibitor For Modification Of GAG Chains And Prevention Of Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$389,778.00
Summary
The major health issue in Australia is vascular and cardiovascular disease resulting from obesity and diabetes. Whilst prevention strategies based on lifestyle changes are preferable, treating cardiovascular risk factors with the latest drugs has been shown to produce significant benefits. There is however a large group of patients who still acquire cardiovascular disease in spite of drug therapy. New therapies are required and these will most likely target blood vessels directly. We have identi ....The major health issue in Australia is vascular and cardiovascular disease resulting from obesity and diabetes. Whilst prevention strategies based on lifestyle changes are preferable, treating cardiovascular risk factors with the latest drugs has been shown to produce significant benefits. There is however a large group of patients who still acquire cardiovascular disease in spite of drug therapy. New therapies are required and these will most likely target blood vessels directly. We have identified a biochemical mechanism that represents a prime target for vascular wall directed therapy and we aim to exploit the therapeutic potential of this pathway by developing a drug to prevent atherosclerosis. A group of large molecules which have recently received increasing attention are the proteoglycans, combined protein-sugar molecules which are heavily coated with negatively charged groups. The binding and retention of lipids in the wall of the blood vessel is the main cause of atherosclerosis. Specifically, the length of the sugar (GAG) chains on the proteoglycans determines the binding of the lipids. We have discovered a new class of inhibitors which directly target proteoglycan synthesis in the vessel wall and greatly reduce the interaction between proteoglycans and lipids. We wish to demonstrate the efficacy of our compound in an animal model with the aim to produce a marked reduction in the rate and extent of development of atherosclerosis. This would lay the foundation for the compound to be taken into human safety trials and subsequently develop an agent for the prevention of atherosclerosis and a thus a reduction in cardiovascular disease.Read moreRead less
Altered Hepatic Pharmacokinetics As A Consequence Of Drug- And Disease-induced Changes In Hepatic Vascularity.
Funder
National Health and Medical Research Council
Funding Amount
$498,088.00
Summary
Many drugs are broken down by the liver or are removed from the liver out into the intestine by the bile, as well as being removed by the kidney and other organs. The effectiveness of the breakdown and removal by the liver depends both on whether the drug can get into the liver cells and on how well the enzymes in the liver are working. Cardiovascular and liver diseases and certain drugs can affect both of these processes. This work is concentrating on those processes which mainly affect the upt ....Many drugs are broken down by the liver or are removed from the liver out into the intestine by the bile, as well as being removed by the kidney and other organs. The effectiveness of the breakdown and removal by the liver depends both on whether the drug can get into the liver cells and on how well the enzymes in the liver are working. Cardiovascular and liver diseases and certain drugs can affect both of these processes. This work is concentrating on those processes which mainly affect the uptake process. The diseases of most interest are liver cirrhosis, fatty liver disease, atherosclerosis and chronic heart failure, all of which together are leading causes of death in Western countries. They are also associated with liver dysfunction due to effects on liver vessels. We have a poor understanding of how the effects of these diseases and a number of drugs on liver vessels affect the functioning of the liver, especially in terms of how they affect drug breakdown or removal of drugs. This project seeks to understand these effects and proposes a number of animal studies as well as human studies to provide insight. The drugs to be studied are those most commonly used in patients with cardiovascular and liver diseases, as one of our main goals is to provide better therapeutic management in these patients.Read moreRead less