Abstract
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.
Highlights
A worldwide upward trend in the burden of noncommunicable diseases such as cancers, stroke, heart and Official journal of the Cell Death Differentiation AssociationSiddeek et al Cell Death Discovery (2019)5:71Page 2 of 14 71 news-room/fact-sheets/detail/obesity-and-overweight) and which are often attributed to excessive intake of calorie-dense food, in particular high-fat diets, and reduced physical activity[1], have consequences in the short term with pregnancy complications, and impact offspring health later during life
At post-natal day 77 (PND77), whereas no difference was detected in the body weight of animals exposed to chow diet (CTRL) or to high-fat diet (HFD), increased heart vs. body weight ratio was induced by maternal exposure to high-fat diet (Fig. 1a)
Since micro-RNAs have been described as effectors of environmental influences on gene expression and disease[20], and because alterations in micro-RNA balance have been reported to induce cardiac hypertrophy and fibrosis, we wondered what could be the role of microRNAs in the cardiac tissular alterations induced by maternal exposure to high-fat diet
Summary
A worldwide upward trend in the burden of noncommunicable diseases such as cancers, stroke, heart and Official journal of the Cell Death Differentiation AssociationSiddeek et al Cell Death Discovery (2019)5:71Page 2 of 14 71 news-room/fact-sheets/detail/obesity-and-overweight) and which are often attributed to excessive intake of calorie-dense food, in particular high-fat diets, and reduced physical activity[1], have consequences in the short term with pregnancy complications, and impact offspring health later during life. Pre-micro-RNAs assembles into a complex constituted by Exportin-5 (XPO5) and RanGTP and translocate into the cytoplasm[14] where they continue their maturation, through a splicing realized by a complex including DICER and TAR RNA-binding protein 2 (TRBP) This results in RNA duplexes comprising the mature micro-RNAs and the passenger strand, microRNAs*15. The micro-RNA biogenesis machinery is sensitive to hormonal regulation and dietary changes[17,18,19] In this context, micro-RNAs and their regulation represent a potential candidate in the understanding of the long-term effects on cardiac functions induced by exposure to nutritional challenges early during development. Based on a human relevant model of cardiac alterations programmed by exposure to maternal high-fat diet, we aimed at delineating the role of micro-RNAs, identifying the defects in the micro-RNA biogenesis machinery in such programming and at highlighting potential targets and approaches for the phenotype reversal
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