Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy

M Schuldt, J Pei, M Harakalova, LM Dorsch, S Schlossarek, M Mokry, JC Knol, TV Pham, T Schelfhorst, SR Piersma, C dos Remedios, M. Dalinghaus, Michelle Michels, FW Asselbergs, MJ Moutin, L Carrier, CR Jimenez, J Velden, DWD Kuster

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Abstract

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, HCMSMNpatients have later disease onset and a better prognosis than HCMSMPpatients. 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 HCMSMPpatients, 11HCMSMNpatients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel MYBPC32373insGmouse 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 HCMSMPthan in HCMSMNand 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

Original languageEnglish
Article numbere007022
Pages (from-to)e007022
JournalCirculation. Heart failure
Volume14
Issue number1
DOIs
Publication statusPublished - 1 Jan 2021

Bibliographical note

Funding Information:
We acknowledge the support from the Netherlands Cardiovascular Research Initiative: An initiative with support of the Dutch Heart Foundation, CVON2014-40 DOSIS and NWO (NWO-ZonMW; 91818602 VICI grant to Dr van der Velden). Dr Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Dr Harakalova is supported by NWO VENI grant (no. 016.176.136). Drs Carrier and Schlossarek are supported by the German Centre for Cardiovascular Research (DZHK), the German Ministry of Research Education (BMBF), the Deutsche Herzstiftung and the Helmut und Charlotte Kassau Stiftung.

Publisher Copyright:
© 2020 American Heart Association, Inc.

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