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
Role For Sphingosine Kinase-1 In Endothelial Progenitor Cell Survival And Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$294,205.00
Summary
Lay description: Collectively, diseases of the vascular system contribute immensely to the burden of health care in Australia. Notably, abnormal blood vessel formation and function (angiogenesis) has been identified as a major cause or contributor to the vascular complications associated with inflammation, cancer, rheumatoid arthritis and diabetes. Endothelial cells are one of the principle cells of blood vessels forming a barrier between the blood and tissues. This project aims to understand th ....Lay description: Collectively, diseases of the vascular system contribute immensely to the burden of health care in Australia. Notably, abnormal blood vessel formation and function (angiogenesis) has been identified as a major cause or contributor to the vascular complications associated with inflammation, cancer, rheumatoid arthritis and diabetes. Endothelial cells are one of the principle cells of blood vessels forming a barrier between the blood and tissues. This project aims to understand the process whereby mature endothelial cells are formed and how replacement of damaged endothelial cells is normally achieved. Stem cell therapy is considered the new frontier for the treatment of many diseases. Understanding how endothelial progenitor cells differentiate to mature endothelial cells and the signals which operate inside the cell may allow therapeutic manipulation of key target moecules in order to limit or control inflammation, tumourigenesis, rheumatoid arthritis and diabetic retinopathy. Our results suggest that one target maybe the enzyme sphingosine kinase.Read moreRead less
Oxidative Stress, Heparan Sulfates And Endothelial Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$450,390.00
Summary
During vascular disease endothelial cells that line the blood lumen are dysfunctional. Growing evidence indicates a role for a protein that the immune system normally uses to destroy infectious agents. This protein accumulates in diseased blood vessels next to endothelial cells. This project will study how this protein causes endothelial dysfunction and test the ability of novel agents to remove this protein from diseased blood vessels to improve endothelial function.
Vascular Effects Of Exercise Training And Lipid-lowering Therapy At Rest And During Exercise In Hypercholesterolaemia
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
The health of the cells which line blood vessels, endothelial cells, is now known to be important in maintaining normal function of the circulation. In patients with elevated blood cholesterol concentration, the function of these cells is abnormal and this is considered to contribute importantly to the blood vessel dysfunction and cardiovascular disease seen in this condition. We have recently demonstrated that drug therapy aimed at decreasing cholesterol concentration in the blood can significa ....The health of the cells which line blood vessels, endothelial cells, is now known to be important in maintaining normal function of the circulation. In patients with elevated blood cholesterol concentration, the function of these cells is abnormal and this is considered to contribute importantly to the blood vessel dysfunction and cardiovascular disease seen in this condition. We have recently demonstrated that drug therapy aimed at decreasing cholesterol concentration in the blood can significantly improve blood vessel function. In other studies we have demonstrated that exercise training improves blood vessel function. The purpose of this research is to determine whether high blood cholesterol impairs exercise capacity by limiting blood flow to exercising muscle. It is also our goal to determine whether exercise training can produce benefit additional to that resulting from lowering cholesterol in those with initially high cholesterol. Blood vessel function will be studied at rest, in response to pharmacological stimulation and during exercise. Vascular function in the forearm will be assessed using synchronised ultrasound (high frequency sound, sonar) and Doppler measures which assess the size of, and flow in, the large artery near the elbow crease. During measurements, procedures are undertaken to alter flow in the arm blood vessels, some depending upon functional ability of the endothelial cells and some independent of those cells. In addition to assessment of blood vessel function, measurements of exercise tolerance will be taken before and after each intervention. By examining the effects of lipid-lowering and exercise training on rest and exercise blood flow responses, this research will help determine the best approach to improving blood vessel function and cardiovascular fitness in patients with high cholesterol.Read moreRead less
Understanding Local And Regional Determinants Of EDHF And NO Dysfunction In Resistance Arteries In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$771,295.00
Summary
Diabetes is a serious and increasing health burden worldwide. Most of the sickness and death associated is due to complications arising in the blood vessels. The inner lining of blood vessels in small arteries uses several different mechanisms to ensure proper blood flow, and in diabetes these are impaired. This study will reveal the cellular mechanisms involved and identify pathways for therapeutic intervention to alleviate the debilitating effects of small artery disease.
Aberrant Oligosaccharide Processing Of Nox2-oxidase As A Mechanism Of Vascular Oxidative Stress In Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$552,565.00
Summary
Excessive production of free radicals by an enzyme called Nox2 may be a cause of artery disease leading to heart attacks and strokes. This study will identify whether the addition of sugarchains to Nox2 causes it to be expressed at the surface of cells allowing the free radicals it produces to exit the cell and cause damage to the blood vessel wall. Charaterising this new pathway of excessive free radical production may pave the way for new diagnostics and treatments for artery disease.
Does Adenotonsillectomy Change Vascular Function In Children With Sleep Breathing Disorders?
Funder
National Health and Medical Research Council
Funding Amount
$522,105.00
Summary
Sleep breathing disorders affect 10% of all children and when severe, obstruction in the upper airways causes serious deficits in growth, development, brain function and heart health. But even mild snoring (without obstruction) may also cause poor health in the arteries that supply blood to the brain and heart, as well as the smaller arteries in the arms and legs. In both adults and children with conditions like diabetes and obesity, poor blood vessel health has been shown to greatly increase th ....Sleep breathing disorders affect 10% of all children and when severe, obstruction in the upper airways causes serious deficits in growth, development, brain function and heart health. But even mild snoring (without obstruction) may also cause poor health in the arteries that supply blood to the brain and heart, as well as the smaller arteries in the arms and legs. In both adults and children with conditions like diabetes and obesity, poor blood vessel health has been shown to greatly increase the future risk of heart attacks, angina and strokes. Children with severe sleep breathing disorders (such as sleep apnoea syndrome) are currently treated by removal of the tonsils and adenoids, which typically resolves snoring and improves sleep, but it is not yet known whether there are any benefits for blood vessel health. The earliest signs of blood vessel disease in children are abnormal function of the lining of the blood vessels (endothelial dysfunction) and thickening of the lining of blood vessels (intima media thickness). They precede the adult diseases of atherosclerosis - which causes heart attacks and strokes, and diabetic kidney and eye disease. These changes can be measured accurately and non-invasively using ultrasound imaging of arteries in the neck and arm. Our primary aim is to assess whether changes in blood vessel health occur in children with sleep breathing disorders across the range of severity, with a secondary aim to measure any changes in cardiovascular control during both sleep (when snoring occurs). Most importantly, by assessing children before and after surgery, we will be able to see for the first time whether treatment of childhood snoring improves blood vessel health. This study may have major implications for the clinical management of snoring children, who may require treatment at an earlier age to prevent poor blood vessel health and an increased risk of cardiovascular diseases later in life.Read moreRead less
Effect Of Pregnancy And Pre-eclampsia On Smooth Muscle And Endothelial Cell Function In Arteries Isolated From Women
Funder
National Health and Medical Research Council
Funding Amount
$194,537.00
Summary
During normal pregnancy the blood vessels of the mother become relaxed. This helps to meet the growing demands of the mother at this time and also ensures sufficient blood supply to the developing fetus. Blood vessels are lined by a single cell layer called the endothelium. The endothelium inactivates a variety of circulating agents which cause arteries to contract, and it also produces potent substances that directly relax the muscle cells in the blood vessel wall. Thus the endothelium plays an ....During normal pregnancy the blood vessels of the mother become relaxed. This helps to meet the growing demands of the mother at this time and also ensures sufficient blood supply to the developing fetus. Blood vessels are lined by a single cell layer called the endothelium. The endothelium inactivates a variety of circulating agents which cause arteries to contract, and it also produces potent substances that directly relax the muscle cells in the blood vessel wall. Thus the endothelium plays an important role in the adaptation of the maternal blood vessels to pregnancy. Insufficient blood supply to the placenta somehow triggers myriad processes including endothelial dysfunction, enhanced clotting of the blood and contraction of the maternal blood vessels, which culminates in the serious disorder of pregnancy known as pre-eclampsia. This condition threatens the health of both mother and fetus, and in Australia, is responsible for 15% of direct maternal deaths and 10% of perinatal mortality. The focus of this project is to study the function of the endothelium and the muscle in the artery wall, and how the function of these entities is altered in the natural adaptation to pregnancy and in pre-eclampsia. The general aim of this study is two fold: (1) to determine how endothelial function adapts to pregnancy and how this is compromised in pre-eclampsia (2) to determine how factors released from the endothelium alone, or in combination with changes in inherent muscle function, alter the state of relaxation and contraction of muscle in the blood vessel wall, and the influence of pregnancy and of pre-eclampsia on these. This project will contribute to a greater understanding of the mechanisms that control the relaxation and contraction of blood vessels in normal pregnancy and those mechanisms that are impaired during pre-eclampsia and thus, may facilitate the development of treatments for this serious disorder.Read moreRead less
Exertional Dyspnoea With Increased Filling Pressure - Mechanisms And Treatment Strategies
Funder
National Health and Medical Research Council
Funding Amount
$387,793.00
Summary
Patients with early heart disease often present with shortness of breath with exercise, as myocardial reserve at that stage is usually sufficient to maintain normal function at rest . Indeed, much myocardial dysfunction may originate from the modern lifestyle, including inactivity, obesity, the metabolic syndrome and type II diabetes. The potential benefits of making a definitive early diagnosis are large, because it seems more likely that an impact can be made on the disease process (and theref ....Patients with early heart disease often present with shortness of breath with exercise, as myocardial reserve at that stage is usually sufficient to maintain normal function at rest . Indeed, much myocardial dysfunction may originate from the modern lifestyle, including inactivity, obesity, the metabolic syndrome and type II diabetes. The potential benefits of making a definitive early diagnosis are large, because it seems more likely that an impact can be made on the disease process (and therefore, outcome) than with late stage disease. Current treatment strategies are expensive and because they are directed at end-organ damage (heart failure, heart attacks etc), rather ineffective. This multispecialty, multidisciplinary group will undertake a series of unique studies aimed at identifying early cardiovascular disease. The strategy will involve detection of abnormal filling behaviour at stress echocardiography, with randomization into longterm and short-term trials to examine various therapeutic strategies. Sensitive new cardiovascular imaging techniques will be used to detect preclinical abnormalities in the structure and function of the heart and vasculature, facilitating a mechanistic understanding of the process of increasing filling pressure with exercise.Read moreRead less