TY - JOUR
T1 - Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy
AU - Schuldt, Maike
AU - Pei, Jiayi
AU - Harakalova, Magdalena
AU - Dorsch, Larissa M.
AU - Schlossarek, Saskia
AU - Mokry, Michal
AU - Knol, Jaco C.
AU - Pham, Thang V.
AU - Schelfhorst, Tim
AU - Piersma, Sander R.
AU - Dos Remedios, Cris
AU - Dalinghaus, Michiel
AU - Michels, Michelle
AU - Asselbergs, Folkert W.
AU - Moutin, Marie-Jo
AU - Carrier, Lucie
AU - Jimenez, Connie R.
AU - van der Velden, Jolanda
AU - Kuster, Diederik W. D.
N1 - Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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, HCMSMN patients have later disease onset and a better prognosis than HCMSMP 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 HCMSMP patients, 11HCMSMN patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel MYBPC32373insG 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 HCMSMP than in HCMSMN 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 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.
AB - 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, HCMSMN patients have later disease onset and a better prognosis than HCMSMP 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 HCMSMP patients, 11HCMSMN patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel MYBPC32373insG 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 HCMSMP than in HCMSMN 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 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.
KW - cardiomyopathies
KW - genotype
KW - heart diseases
KW - mutation
KW - proteomics
KW - treatment
KW - tubulin
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85100279668&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/33430602
UR - http://www.scopus.com/inward/record.url?scp=85100279668&partnerID=8YFLogxK
U2 - 10.1161/CIRCHEARTFAILURE.120.007022
DO - 10.1161/CIRCHEARTFAILURE.120.007022
M3 - Article
C2 - 33430602
VL - 14
JO - Circulation. Heart failure
JF - Circulation. Heart failure
SN - 1941-3289
IS - 1
M1 - e007022
ER -