Long-term impact of maternal high-fat diet on offspring cardiac health: role of micro-RNA biogenesis

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.

A potential probiotic- Lachnospiraceae NK4A136 group: Evidence from the restoration of the dietary pattern from a high-fat diet

“…HFD could also adversely affect the brain by impairing cognitive functions or promoting depression-like symptoms [3][4][5]. Several animal studies have demonstrated that dietary shifts from HFD to a balanced diet could correct adverse effects resulted from HFD with permanent or transgenerational bene ts [6,7].…”

Maternal Exposure to High-Fat Diet Induces Long-Term Derepressive Chromatin Marks in the Heart

“…At PND 77, 18 male rats per group of diet were euthanized with CO 2 . The set of animals used in this study is the same as the one previously described [12].…”

“…During the heart development, these epigenetic mechanisms regulate the different steps involving coordinated cellular proliferation, migration, differentiation and programmed cell death, structural remodeling including looping and septation [11]. As a first step in the understanding of epigenetic programming of adult cardiac diseases by early exposure to nutritional excess, we previously highlighted the potential role of microRNAs in cardiac hypertrophy and fibrosis induced by maternal high-fat diet [12]. The decrease in DiGeorge syndrome critical region 8 (Dgcr8) expression, involved in microRNA biogenesis, seemed to be a critical point in the alterations of the microRNA profile and the transforming growth factor beta (TGFβ)-mediated remodeling induced by maternal exposure to high-fat diet [12].…”

“…As a first step in the understanding of epigenetic programming of adult cardiac diseases by early exposure to nutritional excess, we previously highlighted the potential role of microRNAs in cardiac hypertrophy and fibrosis induced by maternal high-fat diet [12]. The decrease in DiGeorge syndrome critical region 8 (Dgcr8) expression, involved in microRNA biogenesis, seemed to be a critical point in the alterations of the microRNA profile and the transforming growth factor beta (TGFβ)-mediated remodeling induced by maternal exposure to high-fat diet [12]. However, DGCR8 deficiency did not explain the decreased levels of a few microRNAs which indicates that additional mechanisms might be involved in microRNAs regulation and in cardiac pathogenesis driven by maternal exposure to high-fat diet [12].…”

“…The decrease in DiGeorge syndrome critical region 8 (Dgcr8) expression, involved in microRNA biogenesis, seemed to be a critical point in the alterations of the microRNA profile and the transforming growth factor beta (TGFβ)-mediated remodeling induced by maternal exposure to high-fat diet [12]. However, DGCR8 deficiency did not explain the decreased levels of a few microRNAs which indicates that additional mechanisms might be involved in microRNAs regulation and in cardiac pathogenesis driven by maternal exposure to high-fat diet [12]. The accumulation of alterations in multiple epigenetic processes plays an important role in pathogenesis [13] with a greater impact on disease risk than genetic alterations in some tissues [14].…”