Proteomic and functional studies reveal detyrosinated tubulin as treatment target in sarcomere mutation-induced hypertrophic cardiomyopathy
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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 S.; 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.
In: CIRC-HEART FAIL, Vol. 14, No. 1, e007022, 12.01.2021, p. e007022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 S.
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
PY - 2021/1/12
Y1 - 2021/1/12
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.
U2 - 10.1161/CIRCHEARTFAILURE.120.007022
DO - 10.1161/CIRCHEARTFAILURE.120.007022
M3 - SCORING: Journal article
VL - 14
SP - e007022
JO - CIRC-HEART FAIL
JF - CIRC-HEART FAIL
SN - 1941-3289
IS - 1
M1 - e007022
ER -