Siddeek Benazir, Mauduit Claire, Chehade Hassib, Blin Guillaume, Liand Marjorie, Chindamo Mariapia, Benahmed Mohamed, Simeoni Umberto
1Woman-Mother-Child Department, Division of Pediatrics, DOHaD Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
2INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice, France.
Cell Death Discov. 2019 Mar 1;5:71. doi: 10.1038/s41420-019-0153-y. eCollection 2019.
Heart failure is a worldwide leading cause of death. Diet and obesity are particularly of high concern in heart disease etiology. Gravely, altered nutrition during developmental windows of vulnerability can have long-term impact on heart health; however, the underlying mechanisms are poorly understood. In the understanding of the initiation of chronic diseases related to developmental exposure to environmental challenges, deregulations in epigenetic mechanisms including micro-RNAs have been proposed as key events. In this context, we aimed at delineating the role of micro-RNAs in the programming of cardiac alterations induced by early developmental exposure to nutritional imbalance. To reach our aim, we developed a human relevant model of developmental exposure to nutritional imbalance by maternally exposing rat to high-fat diet during gestation and lactation. In this model, offspring exposed to maternal high-fat diet developed cardiac hypertrophy and increased extracellular matrix depot compared to those exposed to chow diet. Microarray approach performed on cardiac tissue allowed the identification of a micro-RNA subset which was down-regulated in high-fat diet-exposed animals and which were predicted to regulate transforming growth factor-beta (TGFβ)-mediated remodeling. As indicated by in vitro approaches and gene expression measurement in the heart of our animals, decrease in DiGeorge critical region 8 (DGCR8) expression, involved in micro-RNA biogenesis, seems to be a critical point in the alterations of the micro-RNA profile and the TGFβ-mediated remodeling induced by maternal exposure to high-fat diet. Finally, increasing DGCR8 activity and/or expression through hemin treatment in vitro revealed its potential in the rescue of the pro-fibrotic phenotype in cardiomyocytes driven by DGCR8 decrease. These findings suggest that cardiac alterations induced by maternal exposure to high-fat diet is related to abnormalities in TGFβ pathway and associated with down-regulated micro-RNA processing. Our study highlighted DGCR8 as a potential therapeutic target for heart diseases related to early exposure to dietary challenge.
心力衰竭是全球主要的死亡原因。饮食和肥胖在心脏病病因中尤其受到高度关注。严重的是，在易受影响的发育窗口期营养改变会对心脏健康产生长期影响；然而，其潜在机制尚不清楚。在理解与发育过程中暴露于环境挑战相关的慢性疾病的起始时，包括微小RNA在内的表观遗传机制失调被认为是关键事件。在此背景下，我们旨在阐明微小RNA在早期发育暴露于营养失衡所诱导的心脏改变编程中的作用。为实现这一目标，我们通过在妊娠和哺乳期给大鼠母体喂食高脂饮食，建立了一个与人类相关的发育暴露于营养失衡的模型。在这个模型中，与喂食普通饮食的后代相比，暴露于母体高脂饮食的后代出现了心脏肥大和细胞外基质沉积增加。对心脏组织进行的微阵列分析鉴定出一个微小RNA子集，该子集在暴露于高脂饮食的动物中下调，并且预计可调节转化生长因子-β（TGFβ）介导的重塑。正如体外实验方法和我们动物心脏中的基因表达测量所示，参与微小RNA生物合成的迪乔治关键区域8（DGCR8）表达降低似乎是微小RNA谱改变以及母体暴露于高脂饮食所诱导的TGFβ介导的重塑的关键点。最后，通过体外血红素处理增加DGCR8活性和/或表达揭示了其在挽救由DGCR8降低驱动的心肌细胞促纤维化表型方面的潜力。这些发现表明，母体暴露于高脂饮食所诱导的心脏改变与TGFβ信号通路异常有关，并与微小RNA加工下调相关。我们的研究强调DGCR8作为与早期暴露于饮食挑战相关的心脏病的潜在治疗靶点。
