Lipoproteins and Atherosclerosis
Dmitri Sviridov
Head, Lipoproteins and Atherosclerosis
dmitri.sviridov@bakeridi.edu.au
Laboratory Overview
Working toward the development of therapeutics to treat atherosclerosis and reduce the incidence of cardiovascular diseases.
It is well documented that cholesterol can be a problem when there is too much of it in the blood, potentially leading to the development of many cardiovascular diseases. The research undertaken by Dmitri Sviridov and his team at Baker IDI aims understand and address this problem by investigating the metabolism of cholesterol and the mechanisms responsible for its accumulation.
Lipoproteins carry cholesterol throughout the bloodstream. In order to be able to travel in the bloodstream, cholesterol is combined with protein to form lipoproteins. Lipoproteins are carrying cholesterol to and from the vessel wall; if too much cholesterol is carried to and too little is carried from the vessel, it accumulates there This accumulated cholesterol causes fatty deposits to build up in the vessel wall, this is known as atherosclerosis.
In the last 10 years, statins, together with maintaining a healthy lifestyle, have been the most effective therapy in treating atherosclerosis by reducing the delivery of cholesterol to the vessel wall. This therapy has been effective in decreasing the incidence of heart disease by as much as 30 per cent. For the remaining 70 per cent whose lives are not saved by statins and maintaining a healthy lifestyle, the research by Dmitri and his team is crucial.
The lipoproteins and atherosclerosis laboratory is investigating the body's natural protective mechanism process which removes excess cholesterol from the vessel wall. This mechanism is dependent on two functions, the cells ability to transfer excess cholesterol to the plasma, and the plasma's capacity to receive excess cholesterol from the cells. Understanding how these functions work, why and how the protective mechanism process breaks down and how to supplement this mechanisms if its activity is insufficient will assist in the development of therapeutics which will restore this process in patients where it is impaired or no longer working.
One of the lab's most significant ongoing projects investigates the development of atherosclerosis in patients with HIV. Advanced treatments in HIV have seen patients living longer lives, and as a result it has become evident that these patients have a higher incidence of heart disease than other members of the community. It was always believed that this higher incidence rate was due to adverse effects of the HIV treatment, as these drugs are known to increase cholesterol in the plasma. However, Dmitri's lab found the HIV virus itself actually shuts down the body's protective mechanism process to such an extent that cells infected with HIV begin accumulating cholesterol making it impossible for them to transfer excess cholesterol to the plasma. The plasma's capacity to receive excess cholesterol from these cells is also significantly affected. In addition it was also found that if the pathway that is causing HIV infected cells to accumulate cholesterol can be controlled, this will not only reduce the development of atherosclerosis in the patient, but will also reduce the activity of the HIV virus.
Research Focus
- Molecular and cellular mechanisms responsible for cholesterol
- Development of new therapeutics to facilitate removal of cholesterol
- Atherosclerosis and infection
- Clinical aspects of cholesterol metabolism
- Atherosclerosis and diabetes
Research Projects
Infection and atherosclerosis
Group Leader: Dr. Nigora Mukhamedova
Cardiovascular disease (CVD) contributes substantially to the overall morbidity of HIV-infected individuals, as 10-30% of these subjects are presented with some form of CVD. The main underlying cause of CVD is atherosclerosis, and factors that are epidemiologically and prospectively the strongest predictors of atherosclerosis are dyslipidemia and impairment of intracellular cholesterol metabolism. Dyslipidemia in HIV-infected patients has been attributed mainly to antiretroviral drugs, in particular protease inhibitors. Our recent studies suggest that HIV infection impairs intracellular cholesterol metabolism and thus itself is a potent pro-atherogenic factor. This finding may have profound implications for treatment strategy. Indeed, if HIV triggers or continuously causes pro-atherogenic changes, the timely treatment of HIV infection may be essential for prevention of cardiovascular complications.
Our studies in collaboration with George Washington University, Washington, DC, USA have suggested that HIV impairs reverse cholesterol transport and metabolism of high density lipoprotein (HDL) and that may be the key mechanism connecting HIV on atherosclerosis. We are currently conducting a study to characterize associated with HIV-1 infection changes in structure, metabolism and functionality of HDL, and to correlate them with the surrogate measures of progression of atherosclerosis in HIV-infected patients. We also investigate the cellular mechanisms responsible for the impairment of cholesterol metabolism due to HIV infection.
A connection between infection and may not be limited to HIV infection. We are conducting a collaborative study with Melbourne University and Sydney University to investigate an impairment of cholesterol metabolism by cytomegalovirus and by the most primitive infection, prions.
Apolipoprotein A-I mimetic peptides as treatment for atherosclerosis
Group Leader: Associate Profesor Dmitri Sviridov
Drugs affecting lipid metabolism have revolutionized the treatment of atherosclerosis reducing the risk of cardiovascular diseases by 30-40%. There is, however, an urgent need for further reduction of the unacceptably high remaining risk of CVD. A most promising direction is complementing reduction in levels of the pro-atherogenic lipoproteins with increasing levels of the anti-atherogenic lipoprotein, high density lipoprotein (HDL), i.e. "HDL Therapy". One type of HDL therapy is the use of amphipathic peptides mimicking the structure of the main protein of HDL, apoA-I.
Peptides mimicking the structure of apoA-I have been described however, there has been, however, no systematic effort in understanding structure-function relationship of these peptides and very little further development from the original apoA-I mimetic peptide, D-4F. Further, the development process has been limited to a single facet of functionality of these peptides. HDL on the other hand displays numerous anti-atherogenic effects.
In collaboration with the National Heart, Lung and Blood Institute we have recently performed an extensive study analyzing the structure-function relationship of novel apoA-I mimetic peptides focusing on assessing how changes in peptide structure affect various anti-atherosclerosis functional properties. This study resulted in establishing a set of "design rules" potentially useful for determining the activity of the peptides toward individual anti-atherogenic properties ascribed to HDL. We found that features maximizing activity of the peptides are different for different functions. Using the design rules we developed, novel classes of peptides were synthesized and are now being tested in animal models and in a clinical study.
The role of the transporter ABCA12 in lipid metabolism and atherosclerosis
Group Leader: Dr. Ying Fu
In collaboration with Monash University and Walter and Elisa Hall Institute we have recently identified the first animal model the human disease Harlequin Ichthyosis (HI), an often lethal defect of lipid transport and barrier function in the skin. We have shown that mutations in the ABCA12 gene result in profound defects in skin function and in the transport and levels of several lipid species. Strikingly we demonstrate defects in cholesterol and other lipid trafficking in fibroblasts and macrophages from these mice. The results of our studies of this rare human disease provide insights into some of the most serious and prevalent diseases and into the basic biological mechanisms which control lipid balance. ABCA12 may play a fundamental role in controlling lipid homeostasis, both in the epidermis and in macrophages, and as a consequence will play a significant role in the aetiology of atherosclerosis and common skin disorders. Furthermore, ABCA12 may represent a novel yet unknown level of regulation of cellular cholesterol homeostasis. We are currently investigating the cellular and molecular mechanisms of the regulation of cholesterol metabolism by ABCA12.
Atherosclerosis and diabetes
Group Leader: Ms. Anh Hoang
It is well known that diabetes is associated with accelerated atherosclerosis. Type 2 diabetes increases the risk of coronary artery disease (CAD) by 2 to 4 times in the overall population. The increased risk of atherosclerosis in diabetes is considered to be multi-factorial. Indeed, for any given cardiovascular risk factor such as hypertension or dyslipidaemia, diabetic subjects have at least a 2 fold increased risk of a vascular event when compared to a normoglycaemic individual. The issue still remains unresolved as to whether diabetes associated atherosclerosis is purely an accelerated form of atherosclerosis or involves some diabetes-specific abnormalities, which lead to more aggressive disease.
Several of the pathophysiologic mechanisms affected by diabetes are also involved in the pathogenesis of atherosclerosis. Endothelial dysfunction, thrombogenesis, oxidative stress, hypertension all may contribute to diabetes-induced atherosclerosis. Dyslipidaemia is considered one of the most important atherogenic factors affected by diabetes and it is clear that, in addition to diabetes-induced changes in plasma lipoprotein profile, there are other diabetic-specific lipid-related factors which contribute to the development of diabetes-induced atherosclerosis. It has been recently demonstrated both an independent and additive contribution of dyslipidaemia and diabetes to the development of atherosclerotic lesions. We are using animal models and clinical studies to investigate how diabetes affects the functionality and metabolism of high density lipoprotein (HDL).
Lab Head Profile
Dmitri Sviridov has been working in the field of atherosclerosis and lipoprotein research for 32 years. From 1978 to 1992 he was working in the National Cardiology Research Centre in Moscow, first as a PhD student and then as a Research Officer and a Senior Research Fellow in charge of the laboratory. During these years his research was focused on interaction of platelets with the vessel wall and cholesterol and lipoprotein metabolism in the human small intestine. In 1993 he joined the Baker Medical Research Institute and moved to Australia. From 1993 Dmitri worked as a Senior Research Officer in the Laboratory of Lipoproteins and Atherosclerosis; in 1999 he was appointed a NHMRC Senior Research Fellow and from 2002 he has been heading the Laboratory of Lipoproteins and Atherosclerosis at the Baker Heart Research Institute. Dmitri is an Associate Professor in the School of Medicine and Pharmacology, University of Western Australia.
Dmitri Sviridov is an author of 126 papers in peer-reviewed scientific journals and books and a co-inventor in 4 international patents. He made many presentations at International meetings, presented numerous Invited Lectures, chaired sessions and was selected for oral presentations at the major International Meetings. Since 1999 Dmitri have been a recipient of 34 grants totaling 12 million dollars (NHMRC, National Heart Foundation, NIH, NMRC, Swiss National Foundation, DART). He is a member of the International and Australian Atherosclerosis Societies, American Heart Association (from 2002 - a Fellow of the American Heart Association), the Australian Society for Medical Research, the Australian Vascular Biology Society and National Association of Research Fellows In 2002-2006 Dmitri was a Director of the Australian Atherosclerosis Society and was involved in organizing AAS section at AMRC in Sydney in 2004 and organizing AAS meetings in 2005 and 2006.
Dmitri's research in the BakerIDI Heart and Diabetes Institute is focused on molecular, cellular and clinical aspects of lipid and lipoprotein metabolism in relation to atherosclerosis and cardiovascular disease. Specifically, it involves studying all aspects of reverse cholesterol transport, intracellular cholesterol trafficking and structural and functional studies of high density lipoprotein. He is also involved in a number of collaborative projects in other Universities in Australia (Monash University, UWA, WEHI and UNSW) as well as internationally (NHLBI/NIH, George Washington University, UCSF, University of Marseilles).
Publication Highlights
Olchawa, B., Kingwell, B. A., Hoang, A., Schneider, L., Miyazaki, O., Nestel, P., Sviridov, D. Physical fitness and reverse cholesterol transport. Arterioscler. Thromb. Vasc. Biol. (2004), v. 24, p. 1087-1091
Mujawar, Z., Rose, H., Morrow, M. P., Pushkarsky, T., Dubrovsky, L., Mukhamedova, N., Dart, A., Fu, Y., Orenstein, J. M., Bobryshev, Y. V., Bukrinsky, M., Sviridov, D. Human Immunodeficiency Virus Impairs Reverse Cholesterol Transport from Macrophages. PLoS Biology (2006), v. 4, p. e365.
Murphy, A. J., Woollard, K. J., Hoang, A, Mukhamedova, N., Stirzaker, R. A., McCormick S. P. A., Remaley, A. T., Sviridov, D. Chin-Dusting, J. High density lipoprotein reduces the human monocyte inflammatory response. Arterioscler. Thromb. Vasc. Biol (2008), v. 28, p. 2071-2077
Smyth, I., Hacking, D. F., Hilton, A. A., Mukhamedova, N., Meikle, P. J., Ellis, S., Collinge, J. E., de Graaf, C. A., Bahlo, M., Sviridov, D., Kile, B. T., Hilton, D. J. A mouse model of Harlequin Ichthyosis delineates a key role for Abca12 in lipid homeostasis. PLoS Genetics (2008), v. 4, p. e1000192
Patel, S., Drew, B. G., Nakhla, S., Duffy, S. J., Murphy, A. J., Barter, P. J., Rye, K-A, Chin-Dusting, J., Hoang, A., Sviridov, D., Celermajer, D. S., Kingwell, B. A. Reconstituted HDL Increases Plasma HDL Anti-Inflammatory Properties and Cholesterol Efflux Capacity in Patients with Type 2 Diabetes. J. Amer. Coll Cardiol. (2009) v. 53, p. 962-971
D'Souza, W., Stonik, J. A., Murphy, A., Demosky, S. J., Sethi, A. A., Moore, X. M., Chin-Dusting, J., Remaley, A. T., Sviridov, D. Structure-function relationships of apolipoprotein A-I mimetic peptides: implications for anti-atherogenic activities of high density lipoprotein. Circ. Res. (2010), v.107,p. 217-227
Scientific Staff
Prof. Paul Nestel
Dr. Nigora Mukhamedova
Dr. Ying Fu
Ms. Anh Hoang
Mr. Hann Low
Ms. Rajitha Kesani
Dr. Michael Ditiatkovski
Students
Ms. Wilissa D'Souza
Ms. Leah Cui
