Cardiac depression after multiple trauma – diagnostic and therapeutic effects of microRNAs

心肌肌钙蛋白的高血清水平反映的心脏损伤经常发生在严重创伤后，并与不良的总体结局相关。创伤后的心脏损伤主要与增强的局部和全身炎症反应以及先天免疫系统的增加的全身激活相关，包括促炎细胞因子、补体激活产物和损伤相关分子模式（DAMP）的释放。局部地，创伤后的心脏损伤的特征在于受损的钙处理、紊乱的线粒体功能、代谢和结构改变、间隙连接病理和细胞凋亡。miRNAs在不同物种的体内和体外心脏病理生理学的各个方面发挥重要作用。创伤后miRNAs的表达有系统性差异。到目前为止，已经描述了miRNA对心脏作用的不同分子机制。钙处理，炎症，细胞凋亡，NLRP 3半胱天冬酶-1诱导的焦亡和间隙连接是由miRNA解决的。然而，miRNAs作为诊断不同物种创伤后心脏损伤的新型生物标志物的潜力及其治疗效果尚未阐明。因此，在拟议的项目中，将评估血液、心脏和尿液中miRNA的存在，并将其与实验性多发性创伤中的心肌损伤相关联。 将使用临床高度相关和可转移的猪和小鼠多发性创伤模型。为了阐明系统性miRNA在创伤后心肌损伤发展中的预后和诊断作用，系统性差异表达的miRNA将与心脏功能、局部心脏损伤、细胞凋亡、亚硝化和氧化应激以及系统性和心肌炎症相关。此外，在来自所选严重损伤患者的血浆中，将与心脏损伤标志物一起检查全身差异表达的miRNA。此外，通过经胸超声心动图和心电图记录（ECG）进行的心脏功能分析将用于量化心脏损伤并与miRNA表达相关。此外，将测试miRNAs/miRNAs的治疗应用在体外人心肌细胞中减轻心肌损伤的潜力。

Heart injury reflected by high serum levels of cardiac troponin frequently occurs after severe trauma and is associated with a poor overall outcome. Cardiac injuries after trauma mainly correlate with an enhanced local and systemic inflammatory response and with increased systemic activation of the innate immune system, including the release of pro-inflammatory cytokines, complement activation products and damage associated molecular patterns (DAMPs). Locally, cardiac damage after trauma is characterized by impaired calcium handling, disturbed mitochondrial function, metabolic and structural alterations, gap junction pathologies and apoptosis. miRNAs were shown to play an important role in various aspects of cardiac pathophysiology in different species in vivo and in vitro. After trauma miRNAs have been demonstrated to be differentially expressed systemically. Thus far, different molecular mechanisms of miRNA action on the heart have been described. Calcium handling, inflammation, apoptosis, NLRP3 caspase-1-induced pyroptosis and gap junctions are addressed by miRNAs. However, the potential of miRNAs as novel biomarkers for diagnosis of cardiac damage after trauma in different species and their therapeutic efficiency have not been elucidated yet. Therefore, in the proposed project the presence of miRNAs in blood, heart and urine will be assessed and correlated with myocardial damage in experimental polytrauma. Clinically highly relevant and transferable models of porcine and murine multiple trauma will be utilized. To shed light on the prognostic and diagnostic role of systemic miRNAs in the development of post-traumatic myocardial damage, systemically differentially expressed miRNA will be correlated with cardiac function, local cardiac damage, apoptosis, nitrosative and oxidative stress and with systemic and myocardial inflammation. Furthermore, in blood plasma from selected severely injured patients systemically differentially expressed miRNAs will be examined together with cardiac damage markers. Also, functional analysis of the heart via transthoracic echocardiography and electrocardiographic recordings (ECG) will be utilized to quantify cardiac damage and correlate with miRNA expression. Furthermore, the therapeutic application of miRNAs/antagomirs will be tested with regard to their potential to alleviate myocardial damage in vitro in human cardiomyocytes.