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Cardiometabolic Diseases Model

Background

The Cardiometabolic Disease Models Core in NHRIS will provide guidance, training and service in cardiometabolic cell and animal disease models needed to support pre-clinical and translational research in the area of Cardiometabolic Diseases including acute myocardial infarction, left ventricular hypertrophy, heart failure with preserved ejection fraction (HFpEF), diabetic cardiomyopathy and peripheral arterial disease.

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      Prof Derek Hausenloy                  Dr Elisa Liehn                   Dr Chrishan Ramachandra    Dr Sauri Hernandez-Resendiz

  

Expertise

Small animal Cardiometabolic Disease models platform (led by Dr Elisa Liehn and Dr Sauri Hernandez-Resendiz)

This platform will support research themes requiring small animal (mice and rats) models for acute myocardial infarction (AMI), ex vivo and simulated ischemia-reperfusion injury, post-infarct left ventricular (LV) remodelling, left ventricular hypertrophy (LVH), diabetic cardiomyopathy (DMC), diabetic peripheral arterial disease (DM PAD), Atherosclerosis, heart failure with preserved ejection fraction (HFpEF). This platform will provide shared facilities for small animal echocardiography, ECG monitoring, pressure-volume (PV) loop analysis, animal histology, animal imaging, microscopy, isolation of cardiomyocytes/endothelial cells/cardiac fibroblasts, and assessment of myofibril mechanics. Services include experimental design and protocol assistance.

Human induced pluripotent stem cell (iPSC) platform (led by Dr Chrishan Ramachandra)

This platform will allow disease modelling of various cardiac diseases including hypertrophic cardiomyopathy (HCM), DMC, and HFpEF. It will provide phenotypic characterisation of iPSC-derived cardiomyocytes and endothelial cells, new insights into underlying pathophysiology, discovery of novel therapeutic targets and treatments, and a platform for screening tool compounds.


Methodology

Small animal Cardiometabolic Disease models platform

- AMI induced by coronary ligation, and post-infarct adverse LV remodelling in mice and rats

- Ex vivo heart perfusion by Langendorff system

- Simulated ischemia-reperfusion injury in vitro assay

- Pressure-overload LVH induced by transverse aortic constriction (TAC) in mice and rats

- PAD induced by femoral artery ligation with peripheral blood flow measured by Periscan in mice and rats.

- Carotid and aortic atherosclerosis induced by carotid-wire injury and high-fat diet in mice and rats.

- Carotid and aortic stenting in models of atherosclerosis in mice and rats.

- Small animal models of HFpEF (high-fat diet and L-NAME)

- Assess cardiac function using echocardiography and PV Loops in mice and rats.

- Assessment of myofibril mechanics using myofibril rig.

- Isolation of cardiomyocytes, cardiac fibroblasts and endothelial cells.

- Histological and microscopic assessment of heart and vascular atheroma tissue and cells.

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Human induced pluripotent stem cell (iPSC) platform

- Generation of human iPSCs and differentiation into cardiomyocytes or endothelial cells.

- Phenotypic characterisation:

(i) Structural features (e.g. hypertrophy, sarcomere organisation, multinucleation);

(ii) Calcium handling and cellular contractility;

(iii) Myofibril mechanics;

(iv) Endothelial function;

(v) Metabolism and bioenergetics.

- Screening platform for tool compounds targeting cardiometabolic disease.

- Screening platform to determine phenotypic significance of new genetic variants (e.g HCM and DCM).


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Research Area

      • Cardioprotection – discovering new treatments from protecting the myocardium from the detrimental effects of acute ischemia/reperfusion injury (following acute myocardial infarction).

      • Developing novel nanoparticles to improve bioavailability and delivery of therapeutics to the ischaemic heart following acute myocardial infarction.

      • Cardiac disease modelling using iPSCs and small animal models - to identify and validate novel treatment targets for cardiomyopathies (e.g. hypertrophic cardiomyopathy, HFpEF, diabetic cardiomyopathy).

      • Peripheral arterial disease – discovering new treatments for preventing the onset and progression of atherosclerosis and for preventing tunica intimal hyperplasia.

      • Develop novel therapeutic for coating stents to prevent post-angioplasty restenosis in coronart and peripheral arterial disease.


            Achievements

            Grants

              1. NHCS Centre Grant - PROgram for Transforming & Evaluating outcomes in CardiomeTabolic disease (PROTECT) 2021-2025

              2. STaR Award - New treatments and strategies to prevent heart failure in diabetes (PI Prof Derek Hausenloy) 2022-2027

              3. NRF CRP - REducing Diabetic macrovascUlar Complications duE to Peripheral Arterial Disease - REDUCE-PAD (PI Prof Derek Hausenloy) 2021-2025    


              Publications

                  1. Penna C, Andreadou I, Aragno M, Beauloye C, Bertrand L, Lazou A, Falcão-Pires I, Bell R, Zuurbier CJ, Pagliaro P, Hausenloy DJ. Effect of hyperglycaemia and diabetes on acute myocardial ischaemia-reperfusion injury and cardioprotection by ischaemic conditioning protocols. Br J Pharmacol. 2020 Jan 27. doi: 10.1111/bph.14993. [Epub ahead of print] Review. IF 7.73.

                  2. Kompa AR, Greening DW, Kong AM, McMillan PJ, Fang H, Saxena R, Wong RCB, Lees JG, Sivakumaran P, Newcomb AE, Tannous BA, Kos C, Mariana L, Loudovaris T, Hausenloy DJ*, Lim SY*. Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction. Cardiovasc Res. 2020 Apr 6:cvaa088. doi: 10.1093/cvr/cvaa088. IF 10.787.

                  3. Ramachandra CJA, Chua J, Cong S, Kp MMJ, Shim W, Wu JC, Hausenloy DJ. Human induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies. Cardiovasc Res. 2020 May 4:cvaa125. doi: 10.1093/cvr/cvaa125. IF 10.787.

                  4. Curaj A, Schumacher D, Rusu M, Staudt M, Li X, Simsekyilmaz S, Jankowski V, Jankowski J, Dumitraşcu AR, Hausenloy DJ, Schuh A, Liehn EA. Neutrophils Modulate Fibroblast Function and Promote Healing and Scar Formation after Murine Myocardial Infarction. Int J Mol Sci. 2020 May 23;21(10):3685. doi: 10.3390/ijms21103685. IF 4.556.

                  5. Kalkhoran S, Kriston-Vizi J, Hernandez-Resendiz S, Crespo-Avilan GE, Rosdah AA, Lees JG, Simoes Da Costa JR, Ling NXY, Holien JK, Samangouei S, Chinda K, Yap EP, Riquelme JA, Ketteler R, Yellon DM, Lim SY, Hausenloy DJ. Hydralazine protects the heart against acute ischemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission. Cardiovasc Res. 2021 Jan 2:cvaa343. doi: 10.1093/cvr/cvaa343. Online ahead of print. IF 10.787.
                      
                  6. Ramachandra CJA, Kp MMJ, Chua J, Hernandez-Resendiz S, Liehn EA, Gan LM, Michaëlsson E, Jonsson MKB, Ryden-Markinhuhta K, Bhat RV, Fritsche-Danielson R, Lin YH, Sadayappan S, Tang HC, Wong P, Shim W, Hausenloy DJ. Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes. Cardiovasc Res. 2021 Mar 10:cvab077. doi: 10.1093/cvr/cvab077. IF 10.787

                  7. Schumacher D, Curaj A, Staudt M, Cordes F, Dumitraşcu AR, Rolles B, Beckers C, Soppert J, Rusu M, Simsekyilmaz S, Kneizeh K, Ramachandra CJA, Hausenloy DJ, Liehn EA. Phosphatidylserine Supplementation as a Novel Strategy for Reducing Myocardial Infarct Size and Preventing Adverse Left Ventricular Remodeling. Int J Mol Sci. 2021 Apr 22;22(9):4401. doi: 10.3390/ijms22094401. IF 4.556.

                  8. Schumacher D, Liehn EA, Nilcham P, Mayan DC, Rattanasopa C, Anand K, Crespo-Avilan GE, Hernandez-Resendiz S, Singaraja RR, Cook SA, Hausenloy DJ. A neutralizing IL-11 antibody reduces vessel hyperplasia in a mouse carotid artery wire injury model. Sci Rep. 2021 Oct 19;11(1):20674. doi: 10.1038/s41598-021-99880-y.

                  9. Tripathi M, Singh BK, Liehn EA, Lim SY, Tikno K, Castano-Mayan D, Rattanasopa C, Nilcham P, Abdul Ghani SAB, Wu Z, Azhar SH, Zhou J, Hernández-Resèndiz S, Crespo-Avilan GE, Sinha RA, Farah BL, Moe KT, De Silva DA, Angeli V, Singh MK, Singaraja RR, Hausenloy DJ, Yen PM. Caffeine prevents restenosis and inhibits vascular smooth muscle cell proliferation through the induction of autophagy. Autophagy. 2022 Jan 11:1-11. doi: 10.1080/15548627.2021.2021494. IF 16.02.