2. Academic Validation
  3. Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes

Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes

  • Cardiovasc Res. 2022 Jan 29;118(2):517-530. doi: 10.1093/cvr/cvab077.
Chrishan J A Ramachandra 1 2,  Myu Mai Ja Kp 1,  Jasper Chua 1 3,  Sauri Hernandez-Resendiz 1 2,  Elisa A Liehn 1,  Ralph Knöll 4 5,  Li-Ming Gan 6,  Erik Michaëlsson 7,  Malin K B Jonsson 7,  Katarina Ryden-Markinhuhta 7,  Ratan V Bhat 8,  Regina Fritsche-Danielson 8,  Ying-Hsi Lin 1 2,  Sakthivel Sadayappan 9,  Hak Chiaw Tang 10,  Philip Wong 10,  Winston Shim 11,  Derek J Hausenloy 1 2 12 13 14
Affiliations

Affiliations

  • 1 National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
  • 2 Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
  • 3 Faculty of Science, National University of Singapore, Singapore, Singapore.
  • 4 Bioscience, Cardiovascular, Renal & Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 5 Department of Medicine (MedH), Integrated Cardio Metabolic Centre (ICMC), Heart and Vascular Theme, Karolinska Institute, Stockholm SE-171 77, Sweden.
  • 6 Early Clinical Development, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 7 Bioscience Cardiovascular, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 8 Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 9 Division of Cardiovascular Health and Disease, Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati, Cincinnati, OH, USA.
  • 10 Department of Cardiology, National Heart Centre Singapore, Singapore, Singapore.
  • 11 Health and Social Sciences Cluster, Singapore Institute of Technology, Singapore, Singapore.
  • 12 Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 13 The Hatter Cardiovascular Institute, University College London, London, UK.
  • 14 Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taichung, Taiwan.
PMID: 33705529 DOI: 10.1093/cvr/cvab077
Abstract

Aims: Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM. Here, we investigated whether myeloperoxidase (MPO) is expressed in cardiomyocytes and provides a novel therapeutic target for alleviating diastolic dysfunction in HCM.

Methods and results: Human cardiomyocytes derived from control-induced pluripotent stem cells (iPSC-CMs) were shown to express MPO, with MPO levels being increased in iPSC-CMs generated from two HCM patients harbouring sarcomeric mutations in the MYBPC3 and MYH7 genes. The presence of cardiomyocyte MPO was associated with higher chlorination and peroxidation activity, increased levels of 3-chlorotyrosine-modified cardiac Myosin binding protein-C (MYBPC3), attenuated phosphorylation of MYBPC3 at Ser-282, perturbed calcium signalling, and impaired cardiomyocyte relaxation. Interestingly, treatment with the MPO inhibitor, AZD5904, reduced 3-chlorotyrosine-modified MYBPC3 levels, restored MYBPC3 phosphorylation, and alleviated the calcium signalling and relaxation defects. Finally, we found that MPO protein was expressed in healthy adult murine and human cardiomyocytes, and MPO levels were increased in diseased hearts with left ventricular hypertrophy.

Conclusion: This study demonstrates that MPO inhibition alleviates the relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. These findings highlight cardiomyocyte MPO as a novel therapeutic target for improving myocardial relaxation associated with HCM, a treatment strategy which can be readily investigated in the clinical setting, given that MPO inhibitors are already available for clinical testing.

Keywords

Cardiac myosin binding protein-C (MYBPC3); Diastolic dysfunction; Human-induced pluripotent stem cells (hiPSCs); Hypertrophic cardiomyopathy (HCM); Myeloperoxidase; Oxidative stress.

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