Glucose Starvation in Cardiomyocytes Enhances Exosome Secretion and Promotes Angiogenesis in Endothelial Cells

Abstract

Cardiomyocytes (CMs) and endothelial cells (ECs) have an intimate anatomical relationship that is essential for maintaining normal development and function in the heart. Little is known about the mechanisms that regulate cardiac and endothelial crosstalk, particularly in situations of acute stress when local active processes are required to regulate endothelial function. We examined whether CM-derived exosomes could modulate endothelial function. Under conditions of glucose deprivation, immortalized H9C2 cardiomyocytes increase their secretion of exosomes. CM-derived exosomes are loaded with a broad repertoire of miRNA and proteins in a glucose availability-dependent manner. Gene Ontology (GO) analysis of exosome cargo molecules identified an enrichment of biological process that could alter EC activity. We observed that addition of CM-derived exosomes to ECs induced changes in transcriptional activity of pro-angiogenic genes. Finally, we demonstrated that incubation of H9C2-derived exosomes with ECs induced proliferation and angiogenesis in the latter. Thus, exosome-mediated communication between CM and EC establishes a functional relationship that could have potential implications for the induction of local neovascularization during acute situations such as cardiac injury.

Role of Autophagy in Angiogenesis Induced by a High-Glucose Condition in RF/6A Cells

“…Bhattacharyya et al [15] found that hyperglycemia-induced tumor growth of breast cancer was impaired by inhibition of angiogenesis, indicating that angiogenesis induced by hyperglycemia was correlated with breast cancer. Garcia et al [16] demonstrated the role of angiogenesis in heart diseases by promoting the angiogenesis of rat cardiomyocytes by glucose starvation. In our research, we found that high glucose could promote the angiogenesis of RF/6A cells, which may be involved in the pathological processes of DR.…”

Exosomes Generated From iPSC-Derivatives

“…Gene Ontology (GO) analysis of exosome cargo identified the molecules, which alters the angiogenic activity of the endothelial cells. In glucose deprived medium, the exosomes were identified to be loaded with functional glucose transporters and glycolytic enzymes, which are internalized by ECs to increase glucose uptake, glycolytic activity, and pyruvate production in recipient cells 27,109 . A paracrine miRNA crosstalk between cardiac fibroblasts (CFs) and cardiomyocytes (CMs) was found to be mediated by the CF secreted miRNA-enriched exosomes.…”

Extracellular Vesicles and MicroRNAs: Their Role in Tumorigenicity and Therapy for Brain Tumors

“…Additionally, miR-451 was shown to be enriched in EVs from other cells including normal cells (Collino et al 2010; Guduric-Fuchs et al 2012; Pigati et al 2010) in contrast to miR-21, calling into question the specificity of action that this microRNA may exert on microglia. Finally, the analysis of transcriptional regulation (primary transcript) of microRNA-451 in recipient cells may shed new light on a described mode of action, as this particular microRNA was found to be dramatically deregulated upon exposure to stress (Ansari et al 2015; Godlewski et al 2010b) and stress also is an additional mechanism of EV secretion/loading (de Jong et al 2012; Garcia et al 2015; Yu et al 2006). The finding that microRNAs naturally enriched in EVs are post-transcriptionally regulated (Koppers-Lalic et al 2014) questions whether such modification (uridylation of 3′ end of microRNA) has an impact on the affinity of target recognition.…”