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

Benazir Siddeek; Claire Mauduit; Hassib Chehade; Guillaume Blin; Marjorie Liand; Mariapia Chindamo; Mohamed Benahmed; Umberto Simeoni

doi:10.1038/s41420-019-0153-y

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

Cell Death Discov. 2019 Mar 1:5:71. doi: 10.1038/s41420-019-0153-y. eCollection 2019.

Authors

Benazir Siddeek¹, Claire Mauduit², Hassib Chehade¹, Guillaume Blin¹, Marjorie Liand¹, Mariapia Chindamo¹, Mohamed Benahmed^#², Umberto Simeoni^#¹

Affiliations

¹ 1Woman-Mother-Child Department, Division of Pediatrics, DOHaD Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
² 2INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice, France.

^# Contributed equally.

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.