Influence Of Flavonoid Structure And Function On Cardiovascular Protection
Funder
National Health and Medical Research Council
Funding Amount
$571,447.00
Summary
The proposed research will further explore the hypothesis that dietary flavonoids can protect against cardiovascular disease. The importance of flavonoid structure for bioactivity needs further study. In addition, metabolic changes to flavonoid structure could have a profound effect on their bioactivity. Therefore, our overall aim is to investigate the effects of individual flavonoids and their metabolites on bioactivity relevant to cardiovascular disease.
The Coronary Vascular Bed, Shear Stress, Endothelial Signalling And Myocyte Electrophysiology
Funder
National Health and Medical Research Council
Funding Amount
$133,774.00
Summary
Physiologic control muscle performance includes a little understood signal from the walls of blood vessels stimulated by pressure and flow which effect muscle function. How this signal operates is controversial. We have developed a model which enables the evaluation of such signalling where changes in flow in the circumflex coronary artery induce easily measured local changes in electrophysiology which are confined to the territory of the circumflex coronary artery and which can be compared with ....Physiologic control muscle performance includes a little understood signal from the walls of blood vessels stimulated by pressure and flow which effect muscle function. How this signal operates is controversial. We have developed a model which enables the evaluation of such signalling where changes in flow in the circumflex coronary artery induce easily measured local changes in electrophysiology which are confined to the territory of the circumflex coronary artery and which can be compared with control values from the left anterior descending coronary artery territory. We propose to use this stable model to evaluate the origin, the transmission agent and the mechanism by which it alters the action potential duration.Read moreRead less
Suppression Of NADPH Oxidase-derived Oxidative Stress By Anti-sense Probes And HDL In Human Vascular Endothelium
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
In Australia, coronary heart disease (CHD) causing heart attacks remains the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, is an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the key cells that form the lining of all arteries, known as the vascular endothelium. By using novel DNA-type molecules (known as anti-sense) develo ....In Australia, coronary heart disease (CHD) causing heart attacks remains the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, is an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the key cells that form the lining of all arteries, known as the vascular endothelium. By using novel DNA-type molecules (known as anti-sense) developed in our laboratory, which block a particular gene causing oxidative stress, we will determine whether this gene is responsible for the formation of oxyradicals in human and mouse cells grown in culture. In addition, we will explore whether this gene is turned on by factors known to be involved in CHD. Finally, we will also investigate whether the good cholesterol known as HDL can act to prevent oxidative stress in human cells, as we discovered it appears to do in living arteries in vivo. If we find it has the same protective effect in endothelium, we will determine how it does this, and which component proteins of the HDL particle are important. This might suggest new treatments to prevent acute events leading to heart attack and stroke, and possibly new applications where damage appears to result from acute oxidative stress, such as in the brain soon after a stroke has occurred. We also have a plan to develop antisense drugs that will target the important gene specifically in the affected endothelium. In addition, we have other specific new drugs that will block this system in arteries. Simultaneously we will be testing the role of this gene in mouse and rabbit models of artery disease, for both our types of drugs might provide valuable new therapeutic agents to target the underlying cause of CHD and not just its symptoms as current drugs do.Read moreRead less
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
Role Of Epigenetic Mechanisms In Diabetic Vascular Complications
Funder
National Health and Medical Research Council
Funding Amount
$438,520.00
Summary
Diabetic complications including heart attacks, strokes, kidney disease and blindness appear to be related to the high glucose (sugar) level but how glucose itself induces end-organ injury remains to be fully determined. In this proposal it is suggested that the long-term damaging effects of glucose relate to its ability to damage the regulation of genes by directly affecting DNA and its covering known as histones. Specifically glucose, possibly by altering certain biochemical pathways called ox ....Diabetic complications including heart attacks, strokes, kidney disease and blindness appear to be related to the high glucose (sugar) level but how glucose itself induces end-organ injury remains to be fully determined. In this proposal it is suggested that the long-term damaging effects of glucose relate to its ability to damage the regulation of genes by directly affecting DNA and its covering known as histones. Specifically glucose, possibly by altering certain biochemical pathways called oxidation pathways, interferes with enzymes which affect the structure of DNA and related molecules resulting in altered expression of many proteins. One of these proteins known as NF kappa B is activated in diabetes, probably by mechanisms involving regulation of these enzymes which play a central role in modifying gene structure. By clarifying the exact mechanisms at a molecular level that mediate the effect of glucose on genes and proteins it will be possible to target these molecules and develop new treatments to prevent, retard or reverse the blood vessel complications that are so common in diabetes.Read moreRead less
Role Of Chromatin Remodelling In Diabetic Renal And Vascular Complications: In Vivo Studies
Funder
National Health and Medical Research Council
Funding Amount
$474,618.00
Summary
Even after diabetics return to improved blood glucose levels after a period of poor blood glucose control, the kidney and blood vessel complications progress. The cause of this metabolic memory remains unexplained. This proposal focuses on sustained changes as a result of prior glucose levels in proteins called histones that are part of the wrapping of DNA. Using a new technique called carrier ChIP we will study histone modifications in the blood vessels and kidneys in diabetes.
Determinants Of Tissue Response To Nitric Oxide In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$385,432.00
Summary
The endothelium, or inner lining layer of blood vessels, exerts a controlling influence on the tendency of blood vessels to constrict or dilate, and on the likelihood that clots will form by aggregation of platelets within the blood vessel. This process is largely mediated by release of nitric oxide (NO) from the endothelium. Importanly, NO is also the active chemical formed when patients are given nitroglycerine (NTG) for the treatment of angina pectoris. There is evidence that conditions predi ....The endothelium, or inner lining layer of blood vessels, exerts a controlling influence on the tendency of blood vessels to constrict or dilate, and on the likelihood that clots will form by aggregation of platelets within the blood vessel. This process is largely mediated by release of nitric oxide (NO) from the endothelium. Importanly, NO is also the active chemical formed when patients are given nitroglycerine (NTG) for the treatment of angina pectoris. There is evidence that conditions predisposing towards development of angina or of heart attacks (such as high cholesterol levels or high blood pressure) are associated with dysfunction of the endothelium, so that less NO is available. The precise cause of this process is uncertain. However, our recent experiments show that in patients with angina, circulating platelets respond poorly to NO. The research to be undertaken will explore the link between blood vessel and platelet function, examing the impact of race (Aboriginals compared to Caucasians) and coronary risk factors. It will also examine the implications of endothelial dysfunction on initial and long-term responses to NTG. The results will shed light on factors predisposing to development of heart attacks, and identify factors preventing optimal responses to anti-anginal treatment.Read moreRead less
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