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

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 .