Cardiology and Therapeutics

Intracellular cholesterol trafficking and HIV disease

We have recently found that HIV infection, and specifically viral protein Nef, causes severe inhibition of cholesterol efflux in macrophages. Macrophages are infected by HIV and play a key role in the development of atherosclerosis. This phenomenon may be a primary cause of the increased risk of atherosclerosis and cardiovascular diseases associated with HIV. Given that cholesterol plays an important role in HIV assembly, it is likely that this phenomenon represents a mechanism for HIV to subvert cellular cholesterol metabolism toward viral replication. Such subversion may be a key part in viral replication and therefore could be a target for anti-HIV intervention. Impairment of cholesterol efflux from macrophages leads to accumulation of intracellular cholesterol and development of atherosclerosis. Therefore, cholesterol efflux impairment in HIV-infected macrophages may contribute to increased risk of coronary artery disease observed in HIV-infected patients. These considerations make it necessary to further investigate both the effect of HIV on cellular cholesterol transport and the effect of changes in cellular cholesterol metabolism on HIV.

In this study we hypothesize that binding of viral protein Nef to cholesterol and redistribution of cholesterol transporter leads to functional impairment of cholesterol efflux and redirection of the flow of cholesterol toward viral assembly. This hypothesis will be tested in in vitro study using macrophages transfected with Nef and Nef mutants. Further we will test in an animal model that impairment of cholesterol efflux by HIV will cause atherosclerosis. As an outcome of this project we expect to establish the molecular mechanism of the effect of HIV on intracellular cholesterol metabolism in vitro and its effect on the development of atherosclerosis in vivo. The project is ran in collaboration of a number of Australian and overseas laboratories.

Obesity and weight loss and lipoprotein metabolism

Atherosclerosis is responsible for over 50% of deaths from heart diseases. Treatment with lipid-lowering drugs such as statins can reduce the risk of heart disease by approximately 30%, but this leaves patients with considerable excess cardiovascular risk compared to non-diabetic individuals. The major casuse of atherosclerosis is an impairement of liporpotein metabolism. This impairement involves a low , which playes a critical role in cardiovascualr protection. The growing body of evidence also suggest that not only HDL concentration, but its functional properties are affected by diabetes and obesity. In this project we aim to elucidate which anti-atherogenic properties of HDL are affected in obesity and reversed by weight loss. This will provide an explanation of some of the excess risk of atherosclerosis seen in obese patients, and define potential targets for therapeutic intervention. Moreover, it was recently found that HDL plays a protective role in some metabolic consequences of the obesity, such as insulin resistance or fat oxidation, making HDL a part of pathogenic pathway in the development of obesity.

This is collaborative project involving several laboratories and various types of obesity. Two clinical models of obesity and weight loss involves fiirst, patients with mild obesity and diet induced weight loss. Second, it involves patients with morbid obesity and surgical wight loss. We ware testing the ability of HDL from plasma of patient and animals to fulfil its anti-atherogenic functions in ex vivo assays.

HDL therapy

High density lipoprotein (HDL, Good Cholesterol) is a well established negative risk factor for the development of atherosclerosis and coronary heart disease. Not surprising therefore that the attempts to pharmacologically elevate plasma levels of HDL are on the forefront of efforts to reduce cardiovascular risk. Several approaches to this goal are being investigated in the Laboratory of Lipoproteins and Atherosclerosis.

One such approach is testing apolipoprotein A-I mimetic peptides, a project run in collaboration with the Section of Lipoprotein metabolism of the National Heart, Lung and Blood Institute, National Institutes of Health, USA. Apolipoprotein A-I (apoA-I) is a key ingredient of HDL and is capable of performing most of its anti-atherogenic functions. Short peptides mimicking structure of apoA-I are also capable of performing many of apoA-I functions, however the exact relationship between structure of the peptides and their capacity to fulfill many complex functions ascribed to HDL is still not clear. Chemists in NIH have produced a series of peptides with systematic changes in their structure and our laboratory is testing functional properties of these peptides in in vitro and in vivo assays. We hope that as a result of this study we will be able not only to understand structure-function relationships in apoA-I mimetic peptides, but to produce an “ideal” peptide able to substitute and supplement HDL in many of its beneficial properties.

Our laboratory also participates in a collaborative effort investigating consequences of the administration of recombinant HDL to patients. Although such preparation are unsuitable for long-term use for reduction of cardiovascular risk, it appears that they have significant beneficial effect in acute coronary events, e.g. to prevent myocardial infarction. The mechanisms of action of recombinant HDL is far from clear and is a subject of our studies.

Collaborative projects

Laboratory of Lipoproteins and Atherosclerosis is involved in a number of collaborative studies with laboratories in Australia (Walter and Elisa Hall Institute, Monash University, University of Western Australia) and overseas (Centre D’Immunologie de Marseille Luminy, Marseille France, George Washington University, Washington, DC, USA, NIH). These projects are targeting fundamental and clinical aspects of biochemistry, cell biology and physiology of reverse cholesterol transport and metabolic aspects of cardiovascular disease.