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

Research output: Contribution to journalArticleAcademic

22 Citations (Scopus)

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 - 2021

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