Journal of Proteomics ( IF 2.8 ) Pub Date : 2020-10-17 , DOI: 10.1016/j.jprot.2020.104018 Sabine Ameling 1 , Julia Bischof 2 , Marcus Dörr 3 , Stephanie Könemann 3 , Klaus Empen 4 , Kerstin Weitmann 5 , Karin Klingel 6 , Daniel Beug 4 , Vishnu Mukund Dhople 1 , Uwe Völker 1 , Elke Hammer 1 , Stephan B Felix 3
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Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and impaired myocardial function. Endomyocardial biopsies (EMB) enable immunohistochemical and molecular characterization of this disease. However, knowledge about specific molecular patterns and their relation to cardiac function in both ventricles is rare. Therefore, we performed a mass spectrometric analysis of 28 paired EMBs of left (LV) and right ventricles (RV) of patients with DCM or suspected myocarditis allowing quantitative profiling of 743 proteins. We analysed associations between protein abundance of LV and RV as well as the echocardiographic parameters LVEF, TAPSE, LVEDDI, and RVEDDI by linear regression models.
Overall, more LV than RV proteins were associated with LV parameters or with RVEDDI. Most LV and RV proteins increasing in level with impairing of LVEF were annotated to structural components of cardiac tissue. Additionally, a high proportion of LV proteins with metabolic functions decreased in level with decreasing LVEF. Results were validated with LV heart sections of a genetic murine heart failure model.
The study shows, that remodelling and systolic dysfunction in DCM is mirrored by distinct alterations in protein composition of both ventricles. Loss of LV systolic function is reflected predominantly by alterations in proteins assigned to metabolic functions in the LV whereas structural remodelling was more obvious in the RV. Alterations related to intermediate filaments were seen in both ventricles and highlight such proteins as early indicators of LV loss of function.
Significance
The present study report protein sets in the RV and the LV being associated with ventricular function and remodelling in DCM. Protein abundances in the LV and the RV emphasize and expand current knowledge on pathophysiological changes in heart failure and DCM. While RV and LV EMBs do not differ concerning diagnostic assessment of inflammatory status and virus persistence, additional information reflecting disease severity associated protein alterations can be gained by EMB protein profiling. RV and LV protein data provided complementary information. The protein pattern of the LV reflects metabolic changes and an impaired energy production, which is associated with the degree of LV systolic dysfunction and remodelling and may yield important information about the disease status in DCM. On the other hand, at this disease stage of DCM with still preserved RV function, RV alterations in structural proteins may reflect myocardial compensatory protective mechanisms for maintenance of structure and cellular function.
The study highlight particular proteins being of interest as heart failure biomarkers in both ventricles which seem to reflect the severity of the disease. Further comparative studies between different HF aetiologies have to evaluate those proteins as markers specific for DCM.
中文翻译：
DCM对人体左右心室的蛋白质变化的分析
扩张型心肌病（DCM）的特征是心室扩大和心肌功能受损。心肌内膜活检（EMB）可对该疾病进行免疫组织化学和分子表征。但是，关于两个脑室中特定分子模式及其与心功能的关系的知识很少。因此，我们对DCM或疑似心肌炎患者的28对配对的左（LV）和右心室（RV）的EMB进行了质谱分析，从而可以定量分析743种蛋白质。我们通过线性回归模型分析了LV和RV的蛋白质丰度以及超声心动图参数LVEF，TAPSE，LVEDDI和RVEDDI之间的关联。
总体而言，与RV参数或RVEDDI相关的LV蛋白多于RV蛋白。随着LVEF受损，大多数LV和RV蛋白水平增加，都标注为心脏组织的结构成分。此外，随着LVEF的降低，具有代谢功能的LV蛋白的比例也随之降低。结果通过基因鼠心力衰竭模型的左心室切面验证。
研究表明，DCM的重塑和收缩功能障碍可通过两个心室蛋白质组成的明显变化反映出来。左室收缩功能的丧失主要通过左室中分配给代谢功能的蛋白质的改变反映出来，而右室的结构重塑更为明显。在两个心室中都发现了与中间丝相关的变化，并突出了这些蛋白作为LV功能丧失的早期指标。
意义
本研究报告RV和LV中的蛋白质组与DCM的心室功能和重塑有关。左室和右室中的蛋白质丰度强调并扩展了有关心力衰竭和DCM的病理生理变化的当前知识。尽管RV和LV EMB在炎症状态和病毒持久性的诊断评估方面没有区别，但是通过EMB蛋白谱分析可以获得反映疾病严重程度相关蛋白改变的其他信息。RV和LV蛋白数据提供了补充信息。左室的蛋白质模式反映了代谢变化和能量产生受损，这与左室收缩功能障碍和重塑的程度有关，并可能产生有关DCM中疾病状态的重要信息。另一方面，
该研究强调了在两个心室中作为心力衰竭生物标记物感兴趣的特定蛋白质，这些蛋白质似乎反映出疾病的严重程度。在不同的HF病因之间进行进一步的比较研究，必须评估那些蛋白质作为DCM特异的标志物。
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