Cardiology and Therapeutics

Associate Professor Xiao-Jun Du
Head, Experimental Cardiology
xiao-jun.du@bakeridi.edu.au

Laboratory Research Overview

The Experimental Cardiology group was established in 1995, when, in a first for Australia, Du shifted his research focus from classical models to genetically modified mouse models. Du's research is pivotal to the work at Baker IDI: application and discovery in vivo is critical to understanding genetic and molecular mechanisms and establishing novel therapies. The use of the genetically modified mice has contributed significantly to cardiovascular disease research. Currently the mouse has become the most commonly used laboratory species for medical research of a variety of fields. Du's laboratory has established and routinely use a range of techniques, including non-invasive echocardiography, in vivo electrophysiology, microminometry (pressure or pressure/volume recording), assessment of arterial compliance, open-chest surgery to induce heart disease models in mice (ischemia/reperfusion, myocardial infarction, cardiac hypertrophy), and heart perfusion.

The importance of mice to cardiovascular disease research is highlighted by a few important findings from Du's studies. In 1997, Du's team discovered that the mouse is the only laboratory species that like humans, develops ventricular wall rupture following acute myocardial infarction (MI). Wall rupture event almost always leads to sudden death and accounts for 5 - 25 per cent of total deaths during the acute phase. While many other areas of heart disease have seen great improvements, post-infarct ventricular rupture has been out of reach of researchers because none of the other species used in heart research develop ruptures after myocardial infarction is induced. Since then a series of studies have been carried out by Du and his lab with findings convincingly showing that cardiac inflammation post-infarction plays a pivotal role in the onset of this complication. Recent findings highlight the significance of certain class of inflammatory cells, such as mononuclear cells and platelets, in this event and the feasibility of preventing rupture by drug or non-drug interventions.

Another key research area by Du is on the peptide hormone relaxin, a study that is continuing and expanding in its collaboration with the Florey Neuroscience Institute. While it has long been known as a reproductive hormone, Du and collaborators have shown that relaxin, which is able to break down collagen in the reproductive system, may also help in reversal of cardiovascular fibrosis, a hallmark of heart disease in humans. The importance of fibrosis in the onset and progression of cardiovascular diseases is well documented but as yet there is no effective drug treatment. Du's research has found that treating animals with relaxin for a short period is able to significantly reduced fibrosis in the heart and large arteries with improvement in function.

Research Focus

• Heart failure
• Ventricular remodelling
• Cardiovascular fibrosis
• Relaxin
• Myocardial ischaemia and infarction
• Cardiac inflammation
• Sympatho-adrenergic signalling

Research Projects

Role of platelets in post-infarct myocardial inflammation and ventricular remodelling

Following acute myocardial ischemia/infarction, inflammatory responses occur and contribute to myocardial damage, chamber dilatation and development of complications. Our recent research has shown that platelets act as an important class of inflammatory cells contributing significantly to whole body and cardiac inflammation. Particularly platelets interact with leukocytes infiltrating into infarcted tissue and promoting regional inflammation (Figure1). Interventions that inhibit platelet activation is effective in reducing the degree of inflammation and relevant complications. Studies are in progress to explore the mechanism and efficacy of anti-platelet drugs in the inhibition of inflammatory responses post myocardial infarction. By molecular imaging technique, research is also on-going to detect signs within the infarcted wall that are known to closely related to the development of rupture as a novel diagnostic tool.

Figure 1: Immunohistochemistry of infarcted mouse heart showing infiltration of mononuclear cells conjugated with multiple platelets (small particles in red colour) 12 hours after myocardial infarction. IZ: infarct zone

Reproductive hormone relaxin is a promising anti-fibrotic drug for cardiovascular diseases

Discovered in 1926, relaxin is known as a peptide hormone important in reproductive physiology. One of its fundamental actions is to regulate extracellular matrix (ECM) proteins in the reproductive organ/tract to accommodate growth of foetus and delivery of newborns.

One of the features of cardiovascular diseases is accumulation of ECM proteins, particularly collagen (fibrosis). We have performed a series of studies demonstrating that a short period of treatment with relaxin is able to reduce the content of collagen in the heart as well as other organs (kidney, lungs). More importantly, we have recently observed partial reversal of large artery fibrosis by relaxin therapy with improved aorta elasticity in spontaneously hypertensive rats, SHR (Figure 2). We are investigating the possibility that anti-fibrotic drugs, like relaxin, can be used for the treatment of hypertension by reducing large artery stiffness. Plans are now underway for a clinical trial testing the efficacy of relaxin in patients with cardiac and large artery fibrosis. This project is in collaboration with the relaxin research group at Florey Neuroscience Institute and Prof AM Dart.

Figure 2: Reversal of collagen content of the aorta of senescent SHR by a 2-week period of treatment with relaxin( R) versus that by vehicle (V). Blue colour indicates collagen by Masson tri-chrome staining.

Non-classic ß-adrenergic signalling mechanisms in the heart in relation to disease progression

Under conditions of cardiovascular diseases, sympathetic nervous system is activated and, through activation of cardiac ß-adrenergic receptors (ß-AR) and its classic signalling protein-kinase A (PKA) pathway, evokes elevation of heart rate and muscle contraction. Long-term sympatho-β-AR activation is associated with detrimental cardiac actions contributing to development of heart failure. However, the molecular mechanisms by which chronic ß-AR activation mediates deleterious consequences remain partially understood. We have been investigating two non-classic signalling pathways utilized by ß-AR that might contribute to disease progression. First, we have documented the coupling of ß-AR with NADPH oxidase-derived oxidative stress and subsequent inflammatory and fibrogenic signalling. Second, our recent study has revealed regulation by ß-AR of cardiac angiogenic signalling. We are investigating the significance of these non-classic signalling pathways in the onset and progression of heart disease.

Autonomic neurocardiac dysregulation in R6/1 transgenic model of Huntington's disease

Huntington's Disease (HD) is a genetic disorder featured by progressive neurodegeneration. Although heart disease is listed among the leading causes of death in HD, its nature is unknown. Abnormal autonomic nervous system (ANS) activity has also been reported in HD; however, the potential cardiac consequences are not addressed. We are studying the cardiac phenotype of a transgenic mouse model of HD (R6/1) with expression of a mutant human huntingtin gene. Male R6/1 and control littermates over a wide-range of age, from pre-, onset, to advanced HD phase. Comprehensive phenotyping experiments will be conducted using methodologies of echocardiography, micromanometry, telemetry recording of electrocardiogram (ECG) and immunohistochemistry. Our recent findings show that R6/1 HD mice exhibit a profound ANS dysfunction leading to unstable cardiac rhythm and arrhythmias. Further studies are warranted to explore this in HD patients and therapeutic intervention. This project is in collaboration with Prof Geoffrey Head and A/Prof Tony Hannan.

Lab Head Profile

Associate Professor Du is the laboratory head of Experimental Cardiology and Mouse Cardiology Research Platform, and NHMRC Senior Research Fellow. He also holds honorary professorships at four universities in China. He completed his medical degree at Chongqing Medical University (China) and PhD at University of Edinburgh (UK). His research has been focusing on heart failure, particularly in the areas of ventricular remodelling, myocardial inflammation, sympathoadrenergic signalling and cardiac fibrosis. He has established extensive collaborations with internal and external research scientists.

Associate Professor Du has published 150 scientific papers. He has been invited on a regular basis to present his works at national and international conferences or institutional seminars, and to contribute to review articles. By invitation, he reviews manuscripts for over 30 international journals and acts as Editor (Cardiovascular) of CEPP. A/Prof Du has supervised 13 PhD/MD students and 20 honours and Advanced Medical Science students.

Achievements/Awards

• 2004 National Heart Foundation Ross Hohnen Award.
• The first lab in Australia with a range of techniques established for research on mouse cardiology.
• Provided proof-of-concept evidence for relaxin as a potent anti-fibrotic agent in the setting of cardiovascular disease.
• Defined the mouse model of post-infarct mechanical complications and identified cardiac inflammation as a key mechanism 
• Documented distinct roles of subtypes of α- and β-adrenoceptors in cardiac pathological hypertrophy

Publication Highlights

• Du XJ, Autelitano D, Dilley R, Percy E, Wang BH, Dart AM, Woodcock E: ß₂-adrenergic receptor overexpression exacerbates development of heart failure after aortic stenosis. Circulation 2000;101;71-77.
• Fang L, Gao XM, Moore XL, Kiriazis H, Su Y, Ming Z, Lim YL, Dart AM, Du XJ. Differences in inflammation, MMP activation and collagen damage account for gender difference in murine cardiac rupture following myocardial infarction. J Mol Cell Cardiol 2007; 43(5):535-44.
• Du XJ, Bathgate RAD, Samuel CS, Dart AM, Summers RJ. Cardiovascular effects of relaxin: from basic science to clinical therapy (invited review). Nat Rev Cardiol 2010;7(1):48-58.
• Xu Q, ChakravortyA, Bathgate RA, Dart AM, Du XJ. Relaxin therapy reverses stiffened large arteries and improves arterial compliance in senescent spontaneously hypertensive rats. Hypertension 2010;55:1260-1266.
• Xu Q, Dalic A, Fang L, Kiriazis H, Ritchie RH, Sim K, Gao XM, Drummond G, Sarwar M, Zhang YY, Dart AM, Du XJ. Myocardial oxidative stress contributes to transgenic ß2-adrenoceptor activation induced cardiomyopathy and heart failure. Br J Pharmacol 2010 Oct 18 (Epub ahead of print).

Staff

Contact

Direct: +613 8532 1267
Email: xiao-jun.du@bakeridi.edu.au