Cardiovascular Inflammation and Redox Biology

Research Overview

The research undertaken in the Cardiovascular Inflammation and Redox Biology laboratory focuses on improving the lives of people living with diabetes by reducing the burden of diabetes-driven cardiovascular diseases; including atherosclerosis, cardiomyopathies and cardiac remodelling post myocardial infarction. Diabetes is a significant risk factor for cardiovascular events with diabetic patients 2-4 times more at risk.

Our research, by identifying novel therapies aimed at lowering oxidative stress and inflammation, is yielding new areas for drug discovery. Additionally, the lab is focussed on designing novel stent coatings to limit diabetes-mediated restenosis and thrombosis. These preclinical studies are important initial steps in understanding how to better tackle the complications that arise as a consequence of this fast-growing health issue, given the growing obesity epidemic and its link to type 2 diabetes.

Specifically, our laboratory has concentrated on understanding the importance of antioxidant defence and has used novel antioxidant mimetics, as well as activators of the oxidant stress regulator Nrf2, to lessen diabetic complications. A further focus has been on gaining insight into how Nrf2 affects the NLRP3 inflammasome, singularly the most important processing platform of pro-inflammatory cytokines known to mediate 'sterile' inflammation in cardiovascular disease. Our current research is identifying small molecule inhibitors of the NLRP3-axis to limit cardiovascular disease.

Research Focus

  • Understanding of fundamental processes impacted by oxidative stress in diabetic cardiovascular complications.
  • Impact of oxidative stress on inflammatory pathways, including NF-κB, Map Kinases, NLRP3-inflammasome activation, caspase-3 maturation, cytokine production and pore-forming GasderminD.
  • Understanding reductive stress and its effect on vascular remodelling.
  • Use of novel activators of Nrf2 to limit diabetic cardiovascular disease.

Staff

Collaborators

  • Prof Mark Cooper, Dept Diabetes, Monash University.
  • Prof Rebecca Ritchie, Monash Institute Pharmaceutical Sciences (MIPS), Monash University
  • Peter Kingshott and Dr Huseyin Sumer, Swinburne University.
  • A/Prof Maxim Artyomov, University Washington, St. Louis, USA.
  • A/Prof James Vince, Inflammation Div. WEHI

Funding

  • Reata Pharmaceuticals
  • Bayer Pharmaceuticals Grant4Indications
  • Diabetes Australia Research Program (DARP) Grants
  • IMPACT Perpetual Grant

Research Outcomes

  • First to demonstrate a role for endogenous antioxidant defence in mitigating diabetes-associated atherosclerosis.
  • First to show that targeting Nrf2 with small molecule mimetics of bardoxolone methyl improves diabetes-associated endothelial function, atherosclerosis and diabetic kidney disease.
  • First to show that small molecule activators of Nrf2, lessen diabetic retinopathy.
  • First to demonstrate a role for NLRP3 inhibition with a specific inhibitor, MCC950, to limit diabetes-associated atherosclerosis.

Research Publications

ORIGINAL ARTICLES:

  • Sharma A, Choi JSY, Stefanovic N, Sharea AA, Simpson D, Vince JE, Murphy A, Ritchie RM, Jandeleit-Dahm K and DE HAAN JB. Specific NLRP3 inhibition protects against diabetes-associated atherosclerosis. Diabetes, 70:772-787, 2021. https://doi.org/10.2337/db20-0357
  • Mathew G, Sharma A, Pickering RJ, Rosado CJ, Lemarie J, Mudgal J, Thampi M, Sebastian S, Jandeleit-Dahm K, DE HAAN JB, Unnikrishnan MK. A novel synthetic small molecule DMFO targets Nrf2 in modulating pro-inflammatory/anti-oxidant mediators to ameliorate inflammation. Free Rad Res. 13:1-18, 2018.  doi: 10.1080/10715762.2018.1533636
  • Tan SM, Deliyanti D, Figgett W, Talia DM, Wilkinson-Berka JL, DE HAAN JB. Ebselen by modulating oxidative stress improves hypoxia-induced macroglial Müller cell and vascular injury in the retina. Exp. Eye Res. 136:1-8, 2015. DOI information: 10.1016/j.exer.2015.04.015
  • Gray SP, Di Marco E, Okabe J, Szyndralewiez C, heintz F, Touyz, R, DE HAAN JB, Koulis C, Wingler K, Cooper ME, Schmidt H, Jandeleit-Dahm KA. Nox1 plays a key role in Diabetes associated atherosclerosis in humans and mice. Circulation, 127(18):1888-902, 2013.
  • Huet O, Ramsey D, Miljavec S, Jenney A, Aubron C, Aprico A, Stefanovic N, Head G, DE HAAN JB, Chin-Dusting J.P.F. Ensuring animal welfare while meeting scientific aims using a murine pneumonia model of septic shock. Shock: 39(6):488-94, 2013. doi: 10.1097/SHK.0b013e3182939831.
  • Tan SM, Stefanovic N, Tan G, Wilkinson-Berka JL and DE HAAN JB. Lack of the Antioxidant Glutathione Peroxidase-1 (GPx1) Exacerbates Retinopathy of Prematurity in Mice. Invest. Ophthalmol. Vis. Sci, 54(1):555-62, 2013 doi: 10.1167/iovs.12-10685.
  • Chew P, Yuen DYC, Stefanovic N, Pete J, Coughlan MT, Jandeleit-Dahm KA, Thomas MC, Rosenfeldt F, Cooper ME and DE HAAN JB. Anti-atherosclerotic and renoprotective effects of Ebselen in the diabetic Apolipoprotein E/GPx1-double knockout mouse. Diabetes 59(12):3198-207, 2010.
  • Chew P., Yuen DYC., Koh P., Stefanovic N., Febbraio MA., Kola I., Cooper ME., DE HAAN JB. Site-Specific Antiatherogenic Effect of the Antioxidant Ebselen in the Diabetic Apolipoprotein E-Deficient Mouse. Art. Thr. Vasc. Biol. 29: 823-830, 2009.
  • Deliyanti D, Alrashdi SF, Tan SM, Meyer C, Ward KW, DE HAAN JB, Wilkinson-Berka JL. Nrf2 activation is a potential therapeutic approach to attenuate diabetic retinopathy. IOVS, 2018 59(2):815-825, 2018 doi: 10.1167/iovs.17-22920.
  • Sharma A, Rizky L, Stefanovic N, Tate M, Ritchie RH, Ward KW, and DE HAAN JB. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activator dh404 protects against diabetes-induced endothelial dysfunction. Cardiovasc. Diabetol, 16(1):33, 1-13, 2017. DOI: 10.1186/s12933-017-0513-y.
  • Huet O, Pickering R, Tekellis C, Latouche C, Long F, Kingwell B, Dickinson BC, Chang CJ, Masters SL, Makay F, Cooper ME, DE HAAN JB. Protective effect of inflammasome activation by hydrogen peroxide during acute pneumonia in a mouse model of septic shock. Crit Care Med. 45(2):e184-e194, 2017. doi: 10.1097/CCM.0000000000002070.
  • Deliyanti D, Lee JY, Petratos S, Meyer CJ, Ward KW, Wilkinson-Berka JL, DE HAAN JB. A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates vasculopathy in mice with ischaemic retinopathy. Clin Sci.130 (15):1375-87, 2016. doi: 10.1042/CS20160068.
  • Sharma A, Yuen DYC, Huet O, Pickering R, Stefanovic N, Bernatchez P and DE HAAN JB.Lack of glutathione peroxidase-1 facilitates a pro-inflammatory and activated vascular endothelium. Vasc Pharmacol. 79:32-42, 2016. doi: 10.1016/ j.vph.2015.11.001.
  • Sharma A, Sellers S,Stefanovic N, Leung C, Tan SM, Huet O, Granville DJ, Cooper ME, Bernatchez P,DE HAAN JB.Direct eNOS activation provides atheroprotection in diabetes-accelerated atherosclerosis, Diabetes, 64(11):3937-50, 2015.  doi: 10.2337/db15-0472.
  • Tan SM, Sharma A, Stefanovic N, DE HAAN JB.Late-intervention study with ebselen in an experimental model of type 1 diabetic nephropathy. Free Radic Res. 49(3):219-27, 2015.
  • Tan SM, Sharma A, Stefanovic N, Yuen DYC, Karagiannis TC, Meyer C, Ward KW, Cooper ME, DE HAAN JB. A derivative of Bardoxolone methyl, dh404, in an inverse dose-dependent manner, lessens diabetes-associated atherosclerosis and improves diabetic kidney disease. Diabetes, 63(9): 3091-103, 2014.
  • Tan SM, Sharma A, Yuen DYC, Stefanovic N, Krippner G, Mugesh G, Chai Z, DE HAAN JB. The modified selenenyl amide, m-hydroxy ebselen, attenuates diabetic nephropathy and diabetes-associated atherosclerosis in ApoE/GPx1 double knockout mice. PLOS ONE July; 8(7): e69193, 2013.
  • Lewis P., Stefanovic N., Pete J., Calkin AC., Giunti S., Thallas-Bonke V., Jandeleit-Dahm KA., Allen TJ., Kola I., Cooper ME.,DE HAAN JB. Lack of the antioxidant enzyme glutathione peroxidase-1 (GPx1) accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice. Circulation 115:2178-2187,2007.

REVIEW ARTICLES:

  • Choi JSY, DE HAAN JB##, Sharma A##. Animal models of diabetes-associated vascular diseases: An update on available models and experimental analysis" Br J Pharmacol. Invited Review. In press, 2021. ## Joint Senior authors.
  • Sharma A, Tate M, Mathew G, Vince JE, Ritchie RH and de Haan JB. Oxidative stress and NLRP3-inflammasome activity as significant drivers of diabetic cardiovascular complications: therapeutic implications. Frontiers in Physiol, 9:114, 2018. doi: 10.3389/fphys.2018.00114, 2018.
  • Pickering RJ, Rosado CJ, Sharma A, Buksh S, Tate M, and de Haan JB. Recent Novel Approaches to Limit Oxidative Stress and Inflammation in Diabetic Complications. Clin Trans Immunol. 7(4):e1016. doi: 10.1002/cti2.1016, 2018.
  • Lindblom R, Higgins, G, Coughlan M, de Haan JB#*. Targeting mitochondria and Reactive oxygen species-driven pathogenesis in Diabetic nephropathy.  Rev. Diab Studies, 12 (1-2):134-156, 2015.
  • Di Marco E, Jha JC, Sharma A, Wilkinson-Berka JL, Jandeleit-Dahm KA, de Haan JB#*. Are reactive oxygen species still the basis for diabetic complications? Clinical Sci, 129, 199–216, 2015.  doi: 10.1042/CS20150093
  • Tan SM and DE HAAN J.B. Combating Oxidative Stress in Diabetic Complications with NRF2 Activators: How much is too much? Redox Report 2014 May; 19(3):107-17.
  • Rosenfeldt F, Wilson M, Lee G, Kure C, Ou R, Braun L, DE HAAN J.B.  Oxidative Stress in Surgery in an Aging Population: Pathophysiology and Therapy. Exp. Gerontol. 48(1):45-54, 2013.  doi: 10.1016/j.exger.2012.03.010.
  • DE HAAN J.B. Limiting reductive stress for treating in-stent stenosis: the heart of the matter? J Clin Invest. 124(12):5092-4, 2014.  doi: 10.1172/JCI79423.
  • Koulis, C, DE HAAN J.B. and Allen T. A focus on specific novel pathways and therapies in experimental diabetic atherosclerosis. Exp. Rev. Cardiovasc. Ther. 10 (3), 323-335, 2012.
  • Sharma A, Bernatchez P and DE HAAN J.B. Targeting endothelial dysfunction in vascular complications associated with diabetes. Int. J. Vascular Medicine 2012: Article ID 750126, 1-12 (2012).
  • DE HAAN J.B. and Cooper ME. Targeted antioxidant therapies in hyperglycemia-mediated endothelial dysfunction. Frontiers in Bioscience 3: 709-29, 2011.

Research Projects

This Research Group doesn't currently have any projects


School Research Themes

Cardiometabolic



Key Contact

For further information about this research, please contact Head of Laboratory Professor Judy de Haan

Department / Centre

Baker Department of Cardiometabolic Health Research

Node

Baker Heart and Diabetes Institute

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