Cardiology and Therapeutics

Professor Jaye Chin-Dusting 
Head, Vascular Pharmacology
jaye.chin-dusting@bakeridi.edu.au

Laboratory Research Overview

The Vascular Pharmacology group studies the relationship between blood vessels and cardiovascular disease. Jaye and her team of researchers have significantly built on the discovery more than 25 years ago that the endothelium - the innermost layer of the blood vessels, separating the blood from the muscle - is not a passive barrier as it had been assumed but in fact a very active structure in its own right. Their work has had high impact in the management of hepatic cirrhosis. This involved restoring gut flora/NO balance and cardiovascular function. The key papers published in the Annals of Int Med (impact factor > 14) have together received over 100 citations and the work provoked independent editorials, clinical trials and clinical case studies changing clinical practice.

Jaye is a recognised leader in the field of lipids and the endothelium as evidenced by numerous invited reviews, plenaries and by her findings influencing clinical management. A recent highlight was work performed by PhD student Andrew Murphy (2006-2009), in collaboration with Associate Professor Dimitri Sviridov, on the anti-inflammatory aspects of high density lipoprotein, which identified a new cellular pathway and functional mechanism for this complex, findings which held up in patient groups such as Tangiers Disease and where a robust, high throughput assay is now used for lead candidate selection in collaboration with other international research organisations as well as with industry.

Another significant research area is in studies of intracellular endothelial L-arginine and identification of new therapeutic targets. The work is particularly focused on the role of the arginase enzyme where, together with post-doctoral fellow Dr Karen Andrews, PhD scholar Sacha Khong and collaborators at NIH (Washington DC, US) we identified that the arginase II isoform is pivotal for NO production and that overexpression leads to worsened atherosclerotic lesions. The group now plans to examine the role of arginase in the therapeutic unmet field of peripheral arterial occlusive.

Another area of interest is in novel biomarkers in vascular inflammation. This builds on the teams' expertise in human endothelium function, and together with Dr Shirley Moore will study the significance of endothelial progenitors, endothelial microparticles and fibrocytes (and their differentiation) in cardiovascular disease including obesity.

Research Focus

• Role of arginase in manipulating intracellular L-arginine for restoration of endothelium function in peripheral occlusive arterial disease and/or coronary vascular disease
• Develop novel vascular anti-inflammation therapy
• Identify new endothelial biomarkers in cardiovascular disease
• Role of nitric oxide and reactive oxygen species in septic shock
• Role of reactive oxygen species and arginase in pressure induced hypertension

Research Projects

Role of arginase in vascular pathologies including peripheral occlusive arterial disease

Group Leader: Dr Karen Andrews

Arginase, a critical enzyme in the hepatic urea cycle, is now also found in endothelial cells. Since L-arginine is a precursor for arginase, our interest pertains particularly to how arginase can influence vascular pathologies either dependently or independently from nitric oxide. Our program of work in this area extends from the potential use of arginase inhibitors as adjunct therapy for nitrate intolerance to targeting specific isoforms in peripheral occlusive arterial disease and atherosclerosis as well as mechanistic studies on its influence in hypertension induced inflammation.

Growth while in the womb and subsequent health of the blood vessels in newborn babies

Group Leader: Dr Michael Skilton

Aortic intima-media thickness (IMT) is considered the best non-invasive measure of structural arterial health in children. Micahel has worked hard to extend this technique to neonates and this is now incorporated in the American Heart Association's recommendations for non-invasive assessment of subclinical atherosclerosis in children and adolescents. Our research in this area focuses on three emerging and poorly characterized risk factors in priority areas that are of marked public health importance and public interest, ie pregnancy and the intrauterine environment as risk factors for mother and infant, nutrition and vascular health in indigenous Australians.

This work applies Michael's expertise in the detection of subclinical atherosclerosis as a means of assessing the importance and strength of these putative cardiovascular risk factors, and for trialling prevention and treatment strategies aimed at improving vascular health and decreasing the global burden of CVD.

Ultrasound of aortic intima-media thickness (IMT) and dot plot of aortic IMT in "appropriate for gestation age" (AGA) and "small for gestational age" (SGA) neonates (MS19).

Studies of novel soluble biomarkers and targets in cardiovascular disease

Group Leaders: Dr Shirley Moore, Dr Yi Fu and Dr Karen Fang

This group focuses on studies of novel circulating biomarkers in cardiovascular disease including obesity. Together with the team's expertise in human endothelium function, the significance of endothelial progenitor cells, endothelial microparticles and circulating endothelial cells are all under current study. Dr Fang's interest in fibrocytes (and their differentiation) in cardiac fibrosis and plaque stability will identify whether these circulating proteins can be predictive of disease severity and Dr Fu's novel work on the role of cav-1 in atherosclerosis have provided some novel leads in potential therapeutic targets.

Reactive oxygen species in septic shock

Group Leader: Dr Olivier Huet

During infectious disease the reponse of the host against pathogens involves innate and adaptive immune responses. In some cases the immune reponse over-compensates and generates an acute and dramatic inflammatory state known as septic shock where major organs such as the liver, kidneys and lungs may be severely compromised, leading to a state commonly referred to as Multiple Organ Dysfunction Syndrome. Despite subtantial clinical and research progress, septic shock remains a very severe disease with a high rate of mortality (from 30 to 50 per cent).

Recently endothelial cells have been postulated to play a key role in the evolution of septic shock leading to multiple organ dysfunction syndrome. Inflammation can render endothelial cells dysfunctional. We hypothesise that septic shock and inflammation forms endothelial reactive oxygen species (ROS), which are unstable and very toxic molecules affecting cell membrane, proteins and DNA. We further postulate that targeting oxidative stress during septic shock is a new, unexplored and promising research area.

Lab Head Profile

Professor Jaye Chin-Dusting 
Head, Vascular Pharmacology

A cardiovascular pharmacologist, Professor Jaye Chin-Dusting's ability to bring research outcomes to clinical application is evidenced by her role as chief investigator of 2 successive NHMRC Programs on Clinical Cardiology as well as 3 NHMRC Centre of Clinical Research Excellence grants. Her overall intent is to advance cardiovascular research in areas of clinical and therapeutic unmet needs with emphasis on drug discovery. All her work is in the area of endothelial pathologies where the effort is in identification of novel targets and biomarkers and restoration of functionality.

Prof Chin-Dusting is Executive Director (Science Strategy & Core) and a member of the highest level leadership group at Baker IDI. She is Co-Leader of the Cardiology & Therapeutics Division, made up of seven major labs, and Head of the Vascular Pharmacology Lab (approximately 15 staff members). Elsewhere she is a Monash University Faculty of Medicine Adjunct Professor. She was Board Director of AMREP AS Pty Ltd (2007-2009) and Executive Member of the High Blood Pressure Research Council of Australia (2005-2007). She has published over 100 papers (average impact factor 5.3) since 2006), including 17 invited reviews (1 in Nature Reviews (2005); 1 cited>100). 

Prof Chin-Dusting's work is strongly peer (NHMRC direct to lab ~4million; others 1.1million since 2005) and industry (1.1million since 2005) funded. She delivered numerous international and national invited lectures, is Convenor of 3 international Satellite Conferences and Program Secretary of 3 national conferences. She was a NHMRC GRP panel member in 2006, 2007, 2008 and 2010, a NHMRC Med Scholarship selection panel member in 2009, and Chair in 2010 and a peer reviewer NHMRC, NHF, HRB (Ireland), NMRC (Singapore), panel member HRC (NZ 2004). As well, Prof Chin-Dusting is a Guest Managing Editor of Frontiers in Bioscience and Current Pharmaceutical Design; Regional Editor, CMRO, UK and on the Editorial Board of 3 other journals. She has trained 14 PhDs and 2 Masters (10 completed; 7 clinicians), 16 BSc Hons students and 8 post-doctoral fellows (6 current; 5 self-funded).

Achievements/Awards

Publication Highlights 

• Huynh NN, Head GA, Khong SML, Mayorov DN, Andrews KL, Lambert G, Kiriazis H, Xu Q, Du XJ, Chin-Dusting JPF. The arginase II knockout mouse displays a hypertensive phenotype despite a decreased vasoconstrictory profile. Hypertension 2009;54(2):294-301.
• Woollard KJ, Suhartoyo A, Harris EE, Eisenhardt SU, Jackson SP, Peter K, Dart AM, Hickey MJ, Chin-Dusting JPF. Pathophysiological levels of soluble P-selectin mediate adhesion of leukocytes to the endothelium through Mac-1 activation. Circulation Research 2008;103(10):1128-38.
• Murphy AJ, Woollard KJ, Hoang A, Mukhamedova N, Stirzaker RA, McCormick SP, Remaley AT, Sviridov D, Chin-Dusting JPF. High-Density Lipoprotein Reduces the Human Monocyte Inflammatory Response. Arteriosclerosis Thrombosis Vascular Biology 2008;28(11):2071-7.
• Chin-Dusting JPF, Mizrahi J, Jennings G, Fitzgerald D. Outlook: finding improved medicines: the role of academic-industrial collaboration. Nature Reviews Drug Discovery 2005;4:891-7.
• Rasaratnam B, Kaye DM, Dudley F, Jennings G, Chin-Dusting JPF. The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial. Annals of Internal Medicine 2003;139(3):186-93.

Key Staff

Contact

Direct +61 3 8532 1505
Email jaye.chin-dusting@bakeridi.edu.au