Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy
| Autor: | Diederik W. D. Kuster, Maike Schuldt, Saskia Schlossarek, Jaco C. Knol, Thang V. Pham, Michiel Dalinghaus, Michelle Michels, Tim Schelfhorst, Connie R. Jimenez, Marie-Jo Moutin, Jolanda van der Velden, Sander R. Piersma, Jiayi Pei, Michal Mokry, Larissa M. Dorsch, Lucie Carrier, Magdalena Harakalova, Cris dos Remedios, Folkert W. Asselbergs |
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| Přispěvatelé: | Amsterdam UMC - Amsterdam University Medical Center, University Medical Center [Utrecht], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), The University of Sydney, Erasmus University Medical Center [Rotterdam] (Erasmus MC), University College of London [London] (UCL), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Moutin, Marie-Jo, Pediatrics, Cardiology, Amsterdam UMC, Physiology, Medical oncology laboratory, Amsterdam Neuroscience - Neurodegeneration, ACS - Heart failure & arrhythmias |
| Rok vydání: | 2021 |
| Předmět: |
Male
Carrier Proteins/genetics Heart disease genotype [SDV]Life Sciences [q-bio] Haploinsufficiency Troponin T/genetics 030204 cardiovascular system & hematology Gene mutation Sarcomere 0302 clinical medicine Cardiomyopathy Hypertrophic/genetics 0303 health sciences heart diseases treatment Hypertrophic cardiomyopathy Sarcomeres/genetics Middle Aged 3. Good health [SDV] Life Sciences [q-bio] ComputingMethodologies_DOCUMENTANDTEXTPROCESSING cardiovascular system Cardiology Female Tyrosine/metabolism medicine.symptom Ventricular Septum/metabolism Cardiology and Cardiovascular Medicine Ventricular Outflow Obstruction/genetics Sarcomeres Adult cardiomyopathies Cardiac function curve medicine.medical_specialty Cardiomyopathy Diastole Ventricular outflow tract obstruction Ventricular Septum macromolecular substances Article Ventricular Outflow Obstruction Myosin Heavy Chains/genetics 03 medical and health sciences proteomics Troponin T Internal medicine Detyrosination Cardiac Myosins/genetics medicine Animals Humans cardiovascular diseases Aged 030304 developmental biology Heart Failure Myosin Heavy Chains Hypertrophic/genetics Animal business.industry Troponin I Original Articles Tubulin/metabolism Cardiomyopathy Hypertrophic medicine.disease Troponin I/genetics Disease Models Animal tubulin Case-Control Studies Disease Models Tyrosine mutation Carrier Proteins business Cardiac Myosins |
| Zdroj: | Circulation. Heart failure Circulation. Heart failure, 2021, 14 (1), ⟨10.1161/CIRCHEARTFAILURE.120.007022⟩ Circulation. Heart failure, 14(1):e007022. Lippincott Williams & Wilkins Circulation. Heart Failure Circ Heart Fail Circulation. Heart failure, 14(1). Lippincott Williams and Wilkins Schuldt, M, Pei, J, Harakalova, M, Dorsch, L M, Schlossarek, S, Mokry, M, Knol, J C, Pham, T V, Schelfhorst, T, Piersma, S R, Dos Remedios, C, Dalinghaus, M, Michels, M, Asselbergs, F W, Moutin, M-J, Carrier, L, Jimenez, C R, van der Velden, J & Kuster, D W D 2021, ' Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy ', Circulation. Heart failure, vol. 14, no. 1, e007022 . https://doi.org/10.1161/CIRCHEARTFAILURE.120.007022 Circulation. Heart failure, Lippincott Williams & Wilkins, 2021, 14 (1), ⟨10.1161/CIRCHEARTFAILURE.120.007022⟩ Circulation. Heart failure, 14(1):e007022. Lippincott Williams and Wilkins |
| ISSN: | 1941-3297 1941-3289 |
| Popis: | Supplemental Digital Content is available in the text. Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCMSMP), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCMSMN). Genotype-specific differences have been reported in cardiac function. Moreover, HCMSMN patients have later disease onset and a better prognosis than HCMSMP patients. To define if genotype-specific derailments at the protein level may explain the heterogeneity in disease development, we performed a proteomic analysis in cardiac tissue from a clinically well-phenotyped HCM patient group. Methods: A proteomics screen was performed in cardiac tissue from 39 HCMSMP patients, 11HCMSMN patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel MYBPC32373insG mouse model was used to confirm functional relevance of our proteomic findings. Results: In all HCM patient samples, we found lower levels of metabolic pathway proteins and higher levels of extracellular matrix proteins. Levels of total and detyrosinated α-tubulin were markedly higher in HCMSMP than in HCMSMN and controls. Higher tubulin detyrosination was also found in 2 unrelated MYBPC3 mouse models and its inhibition with parthenolide normalized contraction and relaxation time of isolated cardiomyocytes. Conclusions: Our findings indicate that microtubules and especially its detyrosination contribute to the pathomechanism of patients with HCMSMP. This is of clinical importance since it represents a potential treatment target to improve cardiac function in patients with HCMSMP, whereas a beneficial effect may be limited in patients with HCMSMN. |
| Databáze: | OpenAIRE |
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