FOXO Proteins And Protection From Cardiac Ischaemic Injury
Funder
National Health and Medical Research Council
Funding Amount
$354,375.00
Summary
Reduced blood supply to the heart can initiate a heart attack that results in damage to the heart muscle. Loss of muscle tissue under these conditions initiates pathological growth of the heart and can eventually lead to the development of heart failure, a major cause of death and disability in western countries. Treatment with growth factors can prevent the acute damage and loss of cells, but these cause detrimental effects on other tissues. For these reasons, it is necessary to establish ways ....Reduced blood supply to the heart can initiate a heart attack that results in damage to the heart muscle. Loss of muscle tissue under these conditions initiates pathological growth of the heart and can eventually lead to the development of heart failure, a major cause of death and disability in western countries. Treatment with growth factors can prevent the acute damage and loss of cells, but these cause detrimental effects on other tissues. For these reasons, it is necessary to establish ways to activate protective pathways in the heart without causing unwanted effects on other tissues. To this end, we have identified for the first time in the heart members of a newly described family of gene regulators that can cause cell death by increasing expression of cytotoxic factors. We showed that these FKHRor FOXO family members are regulated in the heart and that they are active in generating cytotoxic factors. We now plan to establish whether FOXO proteins are involved in causing cell death during heart attack and whether manipulating their activities can be cardioprotective.Read moreRead less
Novel Omega-3 Fatty Acid Epoxides And The Activation Of Cellular Survival Pathways
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Recent studies have reported that foods and oils containing high levels of omega-3 fatty acids have beneficial effects in patients with arthritis and cardiovascular disease. The mechanisms by which these dietary changes produce health benefits are unclear but it is known that omega-3 fatty acids can replace omega-6 and other fatty acids in cells; these omega-6 acids are more common in western diets. A number of enzymes in cells convert fatty acids to oxygenated derivatives and some of these have ....Recent studies have reported that foods and oils containing high levels of omega-3 fatty acids have beneficial effects in patients with arthritis and cardiovascular disease. The mechanisms by which these dietary changes produce health benefits are unclear but it is known that omega-3 fatty acids can replace omega-6 and other fatty acids in cells; these omega-6 acids are more common in western diets. A number of enzymes in cells convert fatty acids to oxygenated derivatives and some of these have potent protective effects that allow cells to survive in the presence of toxic stimuli. We have found that epoxides formed from the omega-3 fatty acid stearidonic acid are extremely potent protective agents in cells - more so that epoxides from omega-6 acids like arachidonic acid. The present project seeks to identify omega-3 fatty acid epoxides with potent and long-lived beneficial effects in cells, relate these properties to those of omega-6 fatty acid epoxides and then understand how the omega-3 epoxides enhance cell survival. The findings will provide a rational basis from which to understand the beneficial effects of dietary modification already seen in clinical studies. By understanding the biochemical and molecular events in cells that are activated by omega-3 fatty acid epoxides we may be able to design therapies, most likely involving changes in dietary fat intake, that could benefit individuals with arthritic, cardiovascular and other conditions. Given the high incidence of these conditions in this country the potential impact of the findings from this project could be highly significant and are consistent with the national research priority healthy ageing.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
Nox4-containing NADPH-oxidase As A Protective Enzyme In The Cerebral Circulation
Funder
National Health and Medical Research Council
Funding Amount
$515,812.00
Summary
Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in a stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent research at the basic level to better understand the processes of normal, and then abnormal, regulation of brain artery function. The project will test the importance of a newly discovered mechanism for increasing brain blood flow. This involves activa ....Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in a stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent research at the basic level to better understand the processes of normal, and then abnormal, regulation of brain artery function. The project will test the importance of a newly discovered mechanism for increasing brain blood flow. This involves activation of an enzyme, Nox4-containing NADPH-oxidase, to generate oxygen radicals which then relax the wall of blood vessels causing the arteries to let more blood through. We believe that this process plays an important role in the normal, healthy maintenance of blood supply to the brain. Furthermore, we propose that the activity of this enzyme is elevated and therefore protective in brain arteries during high blood presure - which is the major risk factor for stroke. We will specifically test whether the activity of this enzyme actually helps to limit the amount of brain death following stroke. We will use a variety of techniques to assess the importance of this enzyme in brain arteries in the living body, and also in isolated segments of brain artery from animals that are either healthy or have diseased brain arteries. The results are expected to provide major new insight into processes that help maintain brain blood flow under normal conditions and after a stroke, and the knowledge gained here should lead to safer therapies to prevent or treat stroke.Read moreRead less
Functional Interplay Of Transcriptional Activators In The Regulation Of The Cytoprotective Human CYP2J2 Gene
Funder
National Health and Medical Research Council
Funding Amount
$480,828.00
Summary
Human cytochrome P450 2J2 (CYP2J2) is expressed in many tissues. This enzyme acts on polyunsaturated fatty acids to form epoxides that control ion fluxes, the size of blood vessels and inflammation, and also help cells to survive the damaging effects of oxygen deprivation and other stresses. So CYP2J2 has an important role in both normal and injured cells. Increasing the amount of CYP2J2 in cells may be extremely valuable in the defence against injury. Until recently, however, no treatments have ....Human cytochrome P450 2J2 (CYP2J2) is expressed in many tissues. This enzyme acts on polyunsaturated fatty acids to form epoxides that control ion fluxes, the size of blood vessels and inflammation, and also help cells to survive the damaging effects of oxygen deprivation and other stresses. So CYP2J2 has an important role in both normal and injured cells. Increasing the amount of CYP2J2 in cells may be extremely valuable in the defence against injury. Until recently, however, no treatments have been able to do this but we now know that the biologically important vitamin A derivative all-trans-retinoic acid (ATRA) can increase CYP2J2 in cells. In this project we will build on this novel finding to develop treatments that increase CYP2J2 in tissues. About 10% of people have a variant CYP2J2 gene that differs from the common form by one nucleotide. This polymorphic variant can decrease the amount of the CYP2J2 enzyme and increase cardiovascular risk. We ve found that this polymorphism is located in a critical control region of the gene and affects how the gene responds to transcription factors. The present project will study in detail the regulation of the CYP2J2 gene and its naturally occurring variant by transcription factors that bind to this control region. We will also test how the polymorphic version of the gene responds to stress stimuli and to treatments like ATRA that increase the amount of the wild-type gene in cells. Studying human gene regulation is difficult because we cannot easily measure their levels in individuals. So we will make transgenic mice to study human CYP2J2 regulation and will test whether the treatments we devise in cells also work in vivo. These studies will help us to design pharmacological strategies to increase CYP2J2 in cells. By maintaining the beneficial effects of CYP2J2, and understanding how these are altered in the variant, a significant outcome of the project could be a new treatment of cardiovascular disease.Read moreRead less