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

Schuldt, Maike; Pei, Jiayi; Harakalova, Magdalena; Dorsch, Larissa M.; Schlossarek, Saskia; Mokry, Michal; Knol, Jaco C.; Pham, Thang V.; Schelfhorst, Tim; Piersma, Sander R.; dos Remedios, Cris; Dalinghaus, Michiel; Michels, Michelle; Asselbergs, Folkert W.; Moutin, Marie-Jo; Carrier, Lucie; Jimenez, Connie R.; van der Velden, Jolanda; Kuster, Diederik W.D.

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).