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Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2022 Jan 29; Vol. 118 (2), pp. 517-530. - Publication Year :
- 2022
-
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.<br />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.<br />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.<br /> (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Subjects :
- Animals
Cardiac Myosins genetics
Cardiac Myosins metabolism
Cardiomyopathy, Hypertrophic enzymology
Cardiomyopathy, Hypertrophic genetics
Cardiomyopathy, Hypertrophic physiopathology
Carrier Proteins genetics
Carrier Proteins metabolism
Cell Line
Disease Models, Animal
Humans
Hypertrophy, Left Ventricular enzymology
Hypertrophy, Left Ventricular genetics
Hypertrophy, Left Ventricular physiopathology
Induced Pluripotent Stem Cells enzymology
Induced Pluripotent Stem Cells pathology
Male
Mice, Inbred C57BL
Mutation, Missense
Myocytes, Cardiac enzymology
Myocytes, Cardiac pathology
Myosin Heavy Chains genetics
Myosin Heavy Chains metabolism
Peroxidase metabolism
Phosphorylation
Reactive Oxygen Species metabolism
Tyrosine analogs & derivatives
Tyrosine metabolism
Mice
Cardiomyopathy, Hypertrophic drug therapy
Enzyme Inhibitors pharmacology
Hypertrophy, Left Ventricular drug therapy
Induced Pluripotent Stem Cells drug effects
Myocardial Contraction drug effects
Myocytes, Cardiac drug effects
Peroxidase antagonists & inhibitors
Ventricular Function, Left drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 118
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 33705529
- Full Text :
- https://doi.org/10.1093/cvr/cvab077