MiR-214-3p Regulates Piezo1, Lysyl Oxidases and Mitochondrial Function in Human Cardiac Fibroblasts.

Cardiac fibroblasts are pivotal regulators of cardiac homeostasis and are essential in the repair of the heart after myocardial infarction (MI), but their function can also become dysregulated, leading to adverse cardiac remodelling involving both fibrosis and hypertrophy. MicroRNAs (miRNAs) are noncoding RNAs that target mRNAs to prevent their translation, with specific miRNAs showing differential expression and regulation in cardiovascular disease. Here, we show that miR-214-3p is enriched in the fibroblast fraction of the murine heart, and its levels are increased with cardiac remodelling associated with heart failure, or in the acute phase after experimental MI. Tandem mass tagging proteomics and in-silico network analyses were used to explore protein targets regulated by miR-214-3p in cultured human cardiac fibroblasts from multiple donors. Overexpression of miR-214-3p by miRNA mimics resulted in decreased expression and activity of the Piezo1 mechanosensitive cation channel, increased expression of the entire lysyl oxidase (LOX) family of collagen cross-linking enzymes, and decreased expression of an array of mitochondrial proteins, including mitofusin-2 (MFN2), resulting in mitochondrial dysfunction, as measured by citrate synthase and Seahorse mitochondrial respiration assays. Collectively, our data suggest that miR-214-3p is an important regulator of cardiac fibroblast phenotypes and functions key to cardiac remodelling, and that this miRNA represents a potential therapeutic target in cardiovascular disease.

Watermelon-Derived Extracellular Vesicles Influence Human Ex Vivo Placental Cell Behavior by Altering Intestinal Secretions.

SCOPE: During pregnancy, mother-to-fetus transfer of nutrients is mediated by the placenta; sub-optimal placental development and/or function results in fetal growth restriction (FGR), and the attendant risk of stillbirth, neurodevelopmental delay, and non-communicable diseases in adulthood. A maternal diet high in fruit and vegetables lowers the risk of FGR but the association cannot be explained fully by known macro- and micronutrients. METHODS AND RESULTS: This study investigates if dietary-derived extracellular vesicles (EVs) can regulate placental function. The study characterizes the microRNA and protein cargo of EVs isolated from watermelon, show they are actively internalized by human intestinal epithelial cells in vitro, use mass spectrometry to demonstrate that they alter the intestinal secretome and bioinformatic analyses to predict the likely affected pathways in cells/tissues distal to gut. Application of the watermelon EV-modified intestinal secretome to human placental trophoblast cells and ex vivo tissue explants affects the trophoblast proteome and key aspects of trophoblast behavior, including migration and syncytialization. CONCLUSION: Dietary-derived plant EVs can modify intestinal communication with distal tissues, including the placenta. Harnessing the beneficial properties of dietary-derived plant EVs and/or exploiting their potential as natural delivery agents may provide new ways to improve placental function and reduce rates of FGR.