Role of genetic and epigenetic alterations in central signaling modules in the pathophysiology of peripartum cardiomyopathy

在过去的十年中，对围产期心肌病（PPCM）背后的病理生理机制的认识稳步增长。PPCM是指在妊娠最后一个月和分娩后几个月内，健康女性发生左心室（LV）收缩功能障碍。我们估计，在德国，大约每1500-2000例妊娠中就有1例受到影响;非洲的“热点”报告的患病率为每100例妊娠中就有1例。尽管对PPCM的认识提高以及最近在治疗和管理方面的进展改善了结局，但患者仍然面临猝死、随后妊娠期间复发和长期依赖心力衰竭药物的高风险。我们发现，不平衡的氧化应激导致生产的血管抑制片段的护理激素催乳素（PRL），16 kDa的PRL，这似乎诱导和驱动PPCM。初步数据表明，16-kDA PRL信号通过纤溶酶原激活物抑制剂-1（派-1）/uPAR系统在PPCM和派-1是上调的血液样本和iPSC衍生的心肌细胞从PPCM患者。派-1在PPCM患者左室功能恢复后仍升高，提示PAI-1可能是PPCM的易感因素。除派-1外，在随访时LV功能恢复的PPCM患者中，其他几种血清因子尚未正常化，表明尽管功能恢复，但仍存在病理机制。循环microRNA（miRNA）似乎有助于PPCM的病理生理学和miRNA阵列显示PPCM患者和健康产后对照之间的许多miRNA的差异表达。最后，这些差异调节的循环miRNA的潜在靶点是STAT 3、派-1和Notch 1信号通路。基于这些数据，我们将致力于以下目标：1）研究派-1在PPCM中的调节机制，并分析派-1上调是否是PPCM发展所必需的。此外，分析派-1是否适合作为PPCM的诊断工具和治疗靶点。2)确定参与炎症、代谢和癌症的循环细胞因子、激素和生长因子的时程，分析PPCM中这些因子失调的调节机制，并分析它们在PPCM急性和长期病理学中的潜在作用。3)分析循环miRNA对PPCM急性和长期病理的潜在作用及其与血清因子谱的潜在关系，以获得对PPCM疾病中急性和持续病理和（表观遗传）调节剂的新见解。4)研究心脏Notch 1信号传导对PPCM保护和愈合的调节（通过miRNA）和作用。本项目旨在提高对PPCM潜在病理机制的理解，提供新的措施来预测长期结局，并为PPCM患者开发新的治疗选择，以实现更好和更稳定的恢复，以限制长期发病率和死亡率。

Over the past decade, knowledge on the pathophysiological mechanisms behind peripartum cardiomyopathy (PPCM) has steadily grown. PPCM is defined as onset of left ventricular (LV) systolic dysfunction in the last month of pregnancy and the months following delivery in previously healthy women. We estimate that around 1 in 1500-2000 pregnancies are affected in Germany; ‘hot spots’ in Africa report a prevalence of 1 in 100 pregnancies. Although increased awareness and recent progress in the treatment and management of PPCM has improved outcomes, patients remain at high risk for sudden death, relapse during subsequent pregnancies and dependence on long-term heart failure medication. We discovered that unbalanced oxidative stress leads to the production of an angiostatic fragment of the nursing hormone prolactin (PRL), the 16-kDa PRL, which appears to induce and drive PPCM. Preliminary data suggest that 16-kDA PRL signals via the plasminogen activator inhibitor-1 (PAI-1)/uPAR system in PPCM and that PAI-1 is up-regulated in blood samples and in iPSC-derived cardiomyocytes from PPCM patients. PAI-1 remains elevated in PPCM patients after recovery of LV function, suggesting that it may be a predisposing factor for PPCM. Beside PAI-1, several additional serum factors had not normalized at follow-up in PPCM patients with recovered LV function, indicating ongoing pathomechanisms despite functional recovery. Circulating microRNAs (miRNA) seem to contribute to the PPCM pathophysiology and a miRNA array showed differential expression of numerous miRNAs between PPCM patients and healthy postpartum controls. Finally, potential targets for these differentially regulated circulating miRNAs are STAT3, PAI-1 and the Notch1 signalling pathway. Based on these data, we will address the following objectives: 1) Investigate regulatory mechanisms for PAI-1 in PPCM and analyse if PAI-1 up-regulation is essential for PPCM development. In addition, analyse whether PAI-1 is suited as a diagnostic tool and therapeutic target in PPCM. 2) Determine the time course of circulating cytokines, hormones and growth factors involved in inflammation, metabolism and cancer, analyse regulatory mechanisms for deregulation of these factors in PPCM, and analyse their potential role in acute and long-term pathologies of PPCM. 3) Analyse the potential role of circulating miRNAs for acute and long-term pathologies of PPCM and their potential relation to the serum factor profile to gain novel insights into acute and on-going pathologies and (epigenetic) modulators in PPCM disease. 4) Investigate the regulation (by miRNAs) and role of cardiac Notch1 signalling for protection and healing in PPCM. The present project aims to improve the understanding of underlying pathomechanisms in PPCM, provide novel measures to predict long-term outcome and develop novel treatment options for PPCM patients towards better and more stable recovery to limit long-term morbidity and mortality.