Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy
Maike Schuldt, Jiayi Pei, Magdaléna Harakaľová, L. M. Dorsch, Saskia Schlossarek, Michal Mokrý, Jaco C. Knol, Thang V. Pham, Tim Schelfhorst, Sander R. Piersma, Cristobal G. dos Remedios, Michiel Dalinghaus, Michelle Michels, Folkert W. Asselbergs, Marie‐Jo Moutin, Lucie Carrier, Connie R. Jiménez, Jolanda van der Velden, Diederik W.D. Kuster
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, HCM SMP ), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCM SMN ). Genotype-specific differences have been reported in cardiac function. Moreover, HCM SMN patients have later disease onset and a better prognosis than HCM SMP 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 HCM SMP patients, 11HCM SMN patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel MYBPC3 2373insG 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 HCM SMP than in HCM SMN 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 HCM SMP . This is of clinical importance since it represents a potential treatment target to improve cardiac function in patients with HCM SMP , whereas a beneficial effect may be limited in patients with HCM SMN .