Cardiac Hypertrophy Group

• 
  Head of Laboratory
  Professor Julie McMullen

  Julie.mcmullen@baker.edu.au

  View researcher's webpage

  +61 3 8532 1194

Research Overview

Our group focuses on understanding heart enlargement, cardiac hypertrophy, through comparisons between models of health and disease: examining the enlarged athletic heart (physiological hypertrophy) in comparison to heart enlargement associated with disease (pathological hypertrophy).

It is well understood that the hearts of athletes grow, the super fit have a heart size greater than the average person. This enlargement is of benefit to them in their training and works to enable them to continue their level of exercise and fitness. When they stop training that healthy heart growth stops and the heart returns to a normal size. Conversely, heart failure patients commonly experience heart growth but this change is devastating. It wreaks havoc and is usually impossible to reverse.

From this observation, the team's research has focused on understanding the changes in the athlete's heart that might benefit people with heart disease, whose heart growth might be caused by hypertension and/or heart failure. Professor McMullen’s studies demonstrate there are changes in genes that occur in people with cardiac hypertrophy associated with heart failure that do not occur in the athlete's heart. She has established that even though there are comparable increases in heart size, there are clear molecular and histological changes between the two. The laboratory continues to identify genes causing heart enlargement that are good for the heart, as opposed to those genes causing heart enlargement with detrimental effects. The laboratory is now developing gene therapy approaches and testing small molecules which target these genes. In doing so she hopes to reproduce the work of the ‘good genes’ in the failing heart. Their research is novel in its suggestion that it is possible to promote and activate 'good' genes in the heart as opposed to just inhibiting ‘bad’ genes that cause the growth of the diseased heart.

The team's research involves:

1.         Understanding mechanisms in genetically modified mouse models of exercise and heart failure.
2.         Testing gene therapy approaches, small molecules and dietary approaches in heart disease mouse models.

Current therapeutics are largely treating heart failure by delaying disease progression. The goal of this team’s research is to improve function of the failing heart and protect it from complications such as atrial fibrillation.

Research focus

• Identify critical genes, proteins and lipids in the athlete's heart that provide protection.
• Identify 'druggable', heart-specific targets.
• Examine whether targeting protective mechanisms in the exercise trained heart can improve function of the failing heart. This is examined using a number of approaches (gene therapy, small molecules, dietary approaches).
• Examine sex differences in the heart.
• To reduce/rescue the incidence of atrial fibrillation.
• Target microRNAs to treat heart failure, atrial fibrillation and diabetic cardiomyopathy.
• Understand how the heart can provide protection against obesity

Staff

• Dr Bianca Bernardo Group Leader
• Dr Kate Weeks Group Leader
• Dr Aya Matsumoto Research Officer
• Dr Jenny Ooi Research Officer
• Dr Yi Ching Chen Research Officer
• Dr Yow Keat Tham Research Officer
• Ms Suzan Yildiz Research Assistant
• Ms Yonali Alexander Research Assistant
• Ms Emma Masterman Research Assistant
• Ms Jieting Luo Research Assistant
• Mr Roger Chooi Research Administration Officer

Preclinical Cardiology Microsurgery & Imaging Platform

• Dr Daniel Donner Research Officer
• Dr Helen Kiriazis Research Officer
• Dr Aascha Brown Technical Officer

Collaborators

Associate Professor Ruby Lin (The Westmead Institute for Medical Research)- Non-coding RNAs e.g. microRNAs
Professor Peter Meikle (Baker Heart and Diabetes Institute)- Lipidomics
Associate Professor Paul Gregorevic (University of Melbourne)- Gene therapy e.g. AAV

Funding

• NHMRC Ideas Grant
  NHMRC Project Grant x 2
  Heart Foundation Vanguard Grant

Research Outcomes

McMullen JR*, Amirahmadi F,Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, Mollica JP, Zhang L, Zhang Y, Shioi T, Buerger A, Izumo S, Jay PY, Jennings GL. Protective effects of exercise and PI3K(p110α) signalling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci USA 104: 612-617, 2007. *Senior & corresponding author

McMullen JR*, Jennings GL. Differences between pathological and physiological cardiac
hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol.
34:255-62, 2007. *Corresponding author

McMullen JR*, Jay PY. PI3K(p110alpha) Inhibitors as Anti-Cancer Agents: Minding the
Heart. Cell Cycle. 6: 910-913, 2007. Invited Review. *Corresponding author

Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman A, McMullen JR, Gustafsson E, Chandraker A,Yuan X, Pu W, Roberts A, Neilson E, Sayegh M, Izumo S, Kalluri R. Fibroblasts Associated with Cardiac Fibrosis Carry Endothelial Imprint: Implication for Endothelial to Mesenchymal Transition. Nat Med. 13:952-61, 2007.

Pretorius L, Owen K, Jennings GL, McMullen JR*. Promoting physiological hypertrophy in the failing heart. Clin Exp Pharmacol Physiol. 35:438-41, 2008. Invited Review. *Corresponding author

Owen K, Pretorius L, McMullen JR*. PI3K and its protective effects in the failing heart.
Clinical Science. 116:365-75, 2009. Invited Refereed Review. *Corresponding author

Pretorius L, Du XJ, Woodcock EA, Kiriazis H, Lin RCY, Marasco S, Medcalf RL, Ming Z, Head GA, Tan J, Cemerlang N, Sadoshima J, Shioi T, Izumo S, Dart AM, Jennings GL, McMullen JR*. Reduced phosphoinositide 3-kinase(p110) increases the susceptibility to atrial fibrillation. The American Journal of Pathology 175:998-1009, 2009. *Corresponding author

Lin RC, Weeks KL, Gao XM, Williams RB, Bernardo BC, Kiriazis H, Matthews VB, Woodcock EA, Bouwman RD, Mollica JP, Speirs HJ, Dawes IW, Daly RJ, Shioi T, Izumo S, Febbraio MA, Du XJ, McMullen JR*. PI3K(p110alpha) protects against myocardial infarction-induced heart failure:  Identification of PI3K-regulated miRNAs and mRNAs.  Arterioscler Thromb Vasc Biol.  30: 724-32, 2010. *Corresponding author

Huynh K*, McMullen JR*, Julius TL, Tan JW, Love JE, Cemerlang N, Kiriazis H, Du XJ, Ritchie RH. Cardiac-specific insulin-like growth factor 1 receptor transgenic expression protects against cardiac fibrosis and diastolic dysfunction in a mouse model of diabetic cardiomyopathy. Diabetes 59: 1512-20, 2010. *Equal first authors

Bernardo BC, Weeks KL, Pretorius L, McMullen JR*. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies.  Pharmacology & Therapeutics 128:191-2272010. *Corresponding author

Weeks KL and McMullen JR*. The Athlete's Heart vs. the Failing Heart: Can Signalling Explain the Two Distinct Outcomes? Physiology 26:97-105, 2011. *Corresponding author

Waardenberg AJ, Bernardo BC, Ng DC, Shepherd PR, Cemerlang N, Sbroggiò M, Wells CA, Dalrymple BP, Brancaccio M, Lin RC, McMullen JR*. PI3K(p110) Directly Regulates Key Components of the Z-disc and Cardiac Structure. J Biol Chem. 286:30837-46, 2011. *Corresponding author

Bernardo BC, Charchar FJ, Lin RC, McMullen JR*. A microRNA guide for clinicians and basic scientists: background and experimental techniques. Heart Lung Circ. 21(3):131-42, 2012. *Corresponding author

Huynh K, Kiriazis H, Du XJ, Love JE, Jandeleit-Dahm KA, Forbes JM, McMullen JR*, Ritchie RH*. Coenzyme Q10 attenuates diastolic dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis in the db/db mouse model of type 2 diabetes. Diabetologia. 55(5):1544-53, 2012. *Co-Senior author

Weeks KL, Gao X, Du XJ, Boey EJ, Matsumoto A, Bernardo BC, Kiriazis H, Cemerlang N, Tan JW, Tham YK, Franke TF, Qian H, Bogoyevitch MA, Woodcock EA, Febbraio MA, Gregorevic P, McMullen JR*.  PI3K(p110α) Is a Master Regulator of Exercise-Induced Cardioprotection and PI3K Gene Therapy Rescues Cardiac Dysfunction. Circ Heart Fail.  5(4): 523-534, 2012.  *Corresponding author

Ritchie RH*, Love JE, Huynh K, Bernardo BC, Henstridge DC, Kiriazis H, Tham YK, Sapra G, Qin C, Cemerlang N, Boey EJ, Jandeleit-Dahm K, Du XJ, McMullen JR*. Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes. Diabetologia. 55(12):3369-81, 2012. *Co-senior & co-corresponding author

Bernardo BC, Gao XM, Winbanks CE, Boey EJ, Tham YK, Kiriazis H, Gregorevic P, Obad S, Kauppinen S, Du XJ, Lin RC, McMullen JR*. Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci USA. 109(43):17615-20, 2012. *Corresponding author

Huynh K, Kiriazis H, Du XJ, Love JE, Gray SP, Jandeleit-Dahm KA, McMullen JR*, Ritchie RH.* Targeting the Upregulation of Reactive Oxygen Species Subsequent to Hyperglycemia Prevents Type 1 Diabetic Cardiomyopathy in Mice. Free Radic Biol Med 60: 307-17, 2013. *Co-senior & co-corresponding author

Huynh K, Bernardo BC, McMullen JR*, Ritchie RH*. Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signalling pathways. Pharmacol Ther. 375-415, 2014.  *Co-senior & co-corresponding author

Ooi JY, Bernardo BC, McMullen JR*. The therapeutic potential of miRNAs regulated in settings of physiological cardiac hypertrophy. Future Med Chem. 6(2):205-22, 2014. *Corresponding author

Bernardo BC*, Gao XM, Tham YK, Kiriazis H, Winbanks CE, Ooi JY, Boey EJ, Obad S, Kauppinen S, Gregorevic P, Du XJ, Lin RC, McMullen JR*. Silencing of miR-34a attenuates cardiac dysfunction in a setting of moderate, but not severe, hypertrophic cardiomyopathy. PLoS One 9(2):e90337, 2014. *Co-corresponding author

Bernardo BC*, Nguyen SS, Winbanks CE, Gao XM, Boey EJ , Tham YK, Kiriazis H, Ooi JY, Porrello ER, Igoor S, Thomas CJ,  Gregorevic P, Lin RC, Du XJ, McMullen JR*. Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy. FASEB Journal 28(12):5097-110, 2014  *Co-corresponding author

Sapra G, Tham YK, Cemerlang N, Matsumoto A, Kiriazis H, Bernardo BC, Henstridge DC, Ooi JYY,  Pretorius L, Boey EJH, Lim L, Sadoshima J, Meikle PJ, Mellet NA, Woodcock EA, Marasco S, Ueyama T, Du XJ, Febbraio MA*, McMullen JR*. The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. Nature Communications 5:5705 doi: 10.1038/ncomms6705, 2014. *Co-corresponding author

McMullen JR, Boey EJ, Ooi JY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signalling. Blood 124(25): 3829-30, 2014.

Tham YK, Bernardo BC*, Ooi JY, Weeks KL, McMullen JR*. Pathophysiology of cardiac hypertrophy and heart failure: signalling pathways and novel therapeutic targets. Arch Toxicol. 89(9):1401-38, 2015. *Co-corresponding author

La Gerche A & McMullen JR. Let's keep running....exercise, basic science and the knowledge gaps. Invited Editorial- Heart, 101:742-4, 2015. Co-published in Br J Sports Med. 50(2):74-6, 2016.

Bernardo BC*, Ooi JY, Lin RC, McMullen JR*. miRNA therapeutics: a new class of drugs with potential therapeutic applications in the heart. Future Med Chem. 7(13):1771-92, 2015. *Co-corresponding author

Bernardo BC, Sapra G, Patterson NL, Cemerlang N, Kiriazis H, Ueyama T, Febbraio MA, McMullen JR. Long-term overexoression of Hsp70 does not protect against cardiac dysfunction and adverse remodeling in a MURC transgenic mouse model with chronic heart failure and atrial fibrillation. PLoS One 10(12):e0145173, 2015.

Bernardo BC, Nguyen SS, Gao XM, Tham YK, Ooi JY, Patterson NL, Kiriazis H, Su Y, Thomas CJ, Lin RC, Du XJ, McMullen JR. Inhibition of miR-154 protects against cardiac dysfunction and fibrosis in a mouse model of pressure overload. Scientific Reports (Nature Publishing Group). 6:22442, 2016.

Bernardo BC, Ooi JY, Matsumoto A, Tham YK, Singla S, Kiriazis H, Patterson NL, Sadoshima J, Obad S, Lin RC, McMullen JR. Sex differences in response to miRNA-34a therapy in mouse models of cardiac disease: identification of sex-, disease- and treatment-regulated miRNAs. J Physiol. 594(20):5959-74, 2016.

Bernardo BC and McMullen J.R. Molecular Aspects of Exercise-induced Cardiac Remodeling. Cardiology Clinics (Invited Review) 34(4):515-30, 2016.

McMullen JR and Drew BG. Long non-coding RNAs (lncRNAs) in skeletal and cardiac muscle: potential therapeutic and diagnostic targets? Clin Sci (Lond). (Invited Review) 130(24): 2245-2256, 2016.*Image of the month (Dec 2017), Portland Press Publishing, Biochem Soc

Ooi JY, Bernerado BC, Singla S, Patterson NL, Lin RC, McMullen JR. Identification of miR-34 regulatory networks in settings of disease and antimiR therapy: Implications for treating cardiac pathology and other diseases. RNA Biol. 14(5):500-513, 2017.

Prakoso D, De Blasio MJ, Qin C, Rosli S, Kiriazis H, Qian H, Du XJ, Weeks KL, Gregorevic P, McMullen JR, Ritchie RH. Phosphoinositide 3-kinase (p110α) gene delivery limits diabetes-induced cardiac NADPH oxidase and cardiomyopathy in a mouse model with established diastolic dysfunction. Clin Sci (Lond). 131(12):1345-1360, 2017.

Weeks KL, Bernardo BC, Ooi JYY, Patterson NL, McMullen JR. The IGF1-PI3K-Akt Signalling Pathway in Mediating Exercise-Induced Cardiac Hypertrophy and Protection. Adv Exp Med Biol. 1000:187-210, 2017.

Tang CPS, McMullen J, Tam C. Cardiac side effects of bruton tyrosine kinase (BTK) inhibitors. Leuk Lymphoma. 59:1554-1564, 2018.

Tham YK, Huynh K, Mellett NA, Henstridge DC, Kiriazis H, Ooi JYY, Matsumoto A, Patterson NL, Sadoshima J, Meikle PJ, McMullen JR. Distinct lipidomic profiles in models of physiological and pathological cardiac remodeling, and potential therapeutic strategies. Biochim Biophys Acta.1863(3):219-234, 2018.

Bernardo BC, Ooi JYY, Weeks KL, Patterson NL, McMullen JR. Understanding Key Mechanisms of Exercise-Induced Cardiac Protection to Mitigate Disease: Current Knowledge and Emerging Concepts. Physiol Rev. 98(1): 419-475, 2018.

Bernardo BC, Weeks KL, Pongsukwechkul T, Gao X, Kiriazis H, Cemerlang N, Boey EJH, Tham YK, Johnson CJ, Qian H, Du XJ, Gregorevic P, McMullen JR. Gene delivery of medium chain acyl-coenzyme A dehydrogenase induces physiological cardiac hypertrophy and protects against pathological remodelling. Clin Sci (Lond). 132(3): 381-397, 2018.

Bass-Stringer S, Bernardo BC, May CN, Thomas CJ, Weeks KL, McMullen JR. Adeno-Associated Virus Gene Therapy: Translational Progress and Future Prospects in the Treatment of Heart Failure. Heart Lung Circ. 27(11):1285-1300, 2018 Review.

Donner DG, Kiriazis H, Du XJ, Marwick TH, McMullen JR. Improving the quality of preclinical research echocardiography: Observations, training and guidelines for measurement. Am J Physiol Heart Circ Physiol. 315(1):H58-H70, 2018.

Bernardo BC, Gregorevic P, Ritchie RH, McMullen JR. Generation of MicroRNA-34 Sponges and Tough Decoys for the Heart: Developments and Challenges. Frontiers in Pharmacology. Sep 21;9:1090. doi: 10.3389/fphar.2018.01090. eCollection 2018.

Tham YK, Bernardo BC, Huynh K, Ooi JYY, Gao XM, Kiriazis H, Giles C, Meikle PJ, McMullen JR. Lipidomic Profiles of the Heart and Circulation in Response to Exercise versus Cardiac Pathology: A Resource of Potential Biomarkers and Drug Targets. Cell Rep. 24(10):2757-2772, 2018.

Bass-Stringer S, Bernardo BC, May CN, Thomas CJ, Weeks KL, McMullen JR, Adeno-Associated Virus Gene Therapy: Translational Progress and Future Prospects in the Treatment of Heart Failure. Heart, Lung and Circulation 27: 1285–1300, 2018.

Weeks KL, Henstridge DC, Salim A, Shaw JE, Marwick TH, McMullen JR. CORP: Practical tools for improving experimental design and reporting of laboratory studies of cardiovascular physiology and metabolism. Am J Physiol Heart Circ Physiol. 317(3):H627-39, 2019.

Prakoso D, De Blasio MJ, Tate M, Kiriazis H, Donner DG, Qian H, Nash D, Deo M, Weeks KL, Parry LJ, Gregorevic P, McMullen JR, Ritchie RH. Enhanced Cardiac Phosphoinositide 3-Kinase (p110α) using Gene Therapy Attenuates Cardiac Remodeling in Type 2 Diabetic Mice. Am J Physiol Heart Circ Physiol. 318:H840-H852, 2020: doi: 10.1152/ajpheart.00632.2019.

Bass-Stringer S, Ooi JYY, McMullen JR. Clusterin is regulated by IGF1–PI3K signalling in the heart: implications for biomarker and drug target discovery, and cardiotoxicity. Arch Toxicol. 2020. doi: 0.1007/s00204-020-02709-2. [Epub ahead of print]

Research Publications

1. Bernardo BC, Weeks KL, Pretorius L, McMullen JR. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies.  Pharmacology & Therapeutics 128:191-2272010.

2. Weeks KL, Gao X, Du XJ, Boey EJ, Matsumoto A, Bernardo BC, Kiriazis H, Cemerlang N, Tan JW, Tham YK, Franke TF, Qian H, Bogoyevitch MA, Woodcock EA, Febbraio MA, Gregorevic P, McMullen JR.  PI3K(p110α) Is a Master Regulator of Exercise-Induced Cardioprotection and PI3K Gene Therapy Rescues Cardiac Dysfunction. Circ Heart Fail.  5(4): 523-534, 2012.

3. Pretorius L, Du XJ, Woodcock EA, Kiriazis H, Lin RCY, Marasco S, Medcalf RL, Ming Z, Head GA, Tan J, Cemerlang N, Sadoshima J, Shioi T, Izumo S, Dart AM, Jennings GL, McMullen JR. Reduced phosphoinositide 3-kinase(p110) increases the susceptibility to atrial fibrillation. The American Journal of Pathology 175:998-1009, 2009.

4. Bernardo BC, Gao XM, Winbanks CE, Boey EJ, Tham YK, Kiriazis H, Gregorevic P, Obad S, Kauppinen S, Du XJ, Lin RC, McMullen JR. Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci USA. 109(43):17615-20, 2012.

5. Sapra G, Tham YK, Cemerlang N, Matsumoto A, Kiriazis H, Bernardo BC, Henstridge DC, Ooi JYY,  Pretorius L, Boey EJH, Lim L, Sadoshima J, Meikle PJ, Mellet NA, Woodcock EA, Marasco S, Ueyama T, Du XJ, Febbraio MA, McMullen JR. The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. Nature Communications 5:5705 doi: 10.1038/ncomms6705, 2014.

6. Bernardo BC, Ooi JYY, Weeks KL, Patterson NL, McMullen JR. Understanding Key Mechanisms of Exercise-Induced Cardiac Protection to Mitigate Disease: Current Knowledge and Emerging Concepts. Physiol Rev. 98(1): 419-475, 2018.

7. Tham YK, Bernardo BC, Huynh K, Ooi JYY, Gao XM, Kiriazis H, Giles C, Meikle PJ, McMullen JR. Lipidomic Profiles of the Heart and Circulation in Response to Exercise versus Cardiac Pathology: A Resource of Potential Biomarkers and Drug Targets. Cell Rep. 24(10):2757-2772, 2018.
Bond ST, Moody SC, Liu Y, Civelek M, Villanueva CJ, Gregorevic P, Kingwell BA, Hevener AL, Lusis AJ, Henstridge DC, Calkin AC, Drew BG. The E3 ligase March5 is a PPARgamma target gene that regulates mitochondria and metabolism in adipocytes. American Journal of Physiology: Endocrinology and Metabolism. 2019;316:E293-E304