Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy.
Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy.
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DOI：
10.1161/circheartfailure.120.007022
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Kuster DWD
中科院分区：
文献类型：
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作者：
Schuldt M;Pei J;Harakalova M;Dorsch LM;Schlossarek S;Mokry M;Knol JC;Pham TV;Schelfhorst T;Piersma SR;Dos Remedios C;Dalinghaus M;Michels M;Asselbergs FW;Moutin MJ;Carrier L;Jimenez CR;van der Velden J;Kuster DWD
文本中提供了补充数字内容。肥厚型心肌病（HCM）是最常见的遗传性心脏病。虽然约50%的HCM患者携带肌节基因突变（肌节突变阳性，HCMSMP），但另一半患者的遗传背景未知（肌节突变阴性，HCMSMN）。基因型特异性差异已被报道在心脏功能。此外，HCMSMN患者比HCMSMP患者具有更晚的疾病发作和更好的预后。为了确定基因型特异性蛋白质水平的脱轨是否可以解释疾病发展的异质性，我们对临床表现型良好的HCM患者组的心脏组织进行了蛋白质组学分析。对39例HCMSMP患者、11例HCMSMN患者和8例非衰竭对照的心脏组织进行蛋白质组学筛查。HCM患者有梗阻性心肌病，左心室流出道梗阻和舒张功能障碍。一种新的MYBPC 32373 insG小鼠模型用于确认我们的蛋白质组学发现的功能相关性。在所有HCM患者样本中，我们发现代谢途径蛋白水平较低，细胞外基质蛋白水平较高。HCMSMP组总α-微管蛋白和脱酪氨酸α-微管蛋白水平明显高于HCMSMN组和对照组。在2个不相关的MYBPC 3小鼠模型中也发现了较高的微管蛋白去酪氨酸，并且其抑制与分离的心肌细胞的孤雌激素标准化收缩和舒张时间有关。我们的研究结果表明，微管，尤其是其去酪氨酸作用与HCMSMP患者的病理机制有关。这具有临床重要性，因为它代表了改善HCMSMP患者心脏功能的潜在治疗靶点，而HCMSMN患者的有益效果可能有限。
Supplemental Digital Content is available in the text. 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. 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. 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. 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.