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
Helix VIII Of G Protein Coupled Receptors Is A Lipid-activated Signalling Sensor
Funder
National Health and Medical Research Council
Funding Amount
$389,250.00
Summary
G protein-coupled receptors (GPCRs) are the largest superfamily of membrane-embedded receptors and represent prime targets for drug development. The molecular basis for their activation and regulation is poorly understood, particularly the contribution of the membrane environment to receptor function. Using a range of molecular and biophysical approaches and the angiotensin receptor as a model GPCR, studies are proposed to understand the role of the cell membrane in GPCR activation. The results ....G protein-coupled receptors (GPCRs) are the largest superfamily of membrane-embedded receptors and represent prime targets for drug development. The molecular basis for their activation and regulation is poorly understood, particularly the contribution of the membrane environment to receptor function. Using a range of molecular and biophysical approaches and the angiotensin receptor as a model GPCR, studies are proposed to understand the role of the cell membrane in GPCR activation. The results will provide important new information on the molecular mechanism of GPCR regulation and exciting new approaches for drug design.Read moreRead less