Non-coding RNAs in Cardiac Intercellular Communication

Abstract

Intercellular communication allows for molecular information to be transferred from cell to cell, in order to maintain tissue or organ homeostasis. Alteration in the process due to changes, either on the vehicle or the cargo information, may contribute to pathological events, such as cardiac pathological remodeling. Extracellular vesicles (EVs), namely exosomes, are double-layer vesicles secreted by cells to mediate intercellular communication, both locally and systemically. EVs can carry different types of cargo, including non-coding RNAs (ncRNAs), which, are major regulators of physiological and pathological processes. ncRNAs transported in EVs are functionally active and trigger a cascade of processes in the recipient cells. Upon cardiac injury, exosomal ncRNAs can derive from and target different cardiac cell types to initiate cellular and molecular remodeling events such as hypertrophic growth, cardiac fibrosis, endothelial dysfunction, and inflammation, all contributing to cardiac dysfunction and, eventually, heart failure. Exosomal ncRNAs are currently accepted as crucial players in the process of cardiac pathological remodeling and alterations in their presence profile in EVs may attenuate cardiac dysfunction, suggesting that exosomal ncRNAs are potential new therapeutic targets. Here, we review the current research on the role of ncRNAs in intercellular communication, in the context of cardiac pathological remodeling.

Keywords: cardiac intercellular communication; cardiac pathological remodeling; extracellular vesicles; heart failure; non-coding RNAs.

FIGURE 1

Classes of RNAs and their mechanisms of action. In our genome, approximately 98% of the transcribed RNA is ncRNA, a diverse class of RNAs that does not encode for a protein. ncRNAs are divided according to their localization: nucleus or cytoplasm; shape: circular or linear and size: small or long. Each ncRNA is a unique form and mechanism of action, as described inside of each box. In this review we focused on microRNAs, long non-coding, and circular RNAs. Dashed lines represent findings that need further validation.

FIGURE 2

Intercellular transfer of ncRNAs during cardiac pathological remodeling. Cardiac pathological stimuli promote the various cardiac cell types to release exosomes that are enriched in several ncRNA species including miRs, circRNAs, and lncRNAs. Intercellular transfer of ncRNAs in the heart regulates diverse types of remodeling cellular and molecular processes in the recipient cells (cardiomyocytes, endothelial cells, cardiac fibroblasts, inflammatory, and mesenchymal stem cells), contributing to cardiac hypertrophy, microvascular dysfunction, capillary rarefaction, fibrosis, and inflammation. Intercellular communication is a bidirectional complex and the direction of the arrows represents the direction of the transference. Colors of the arrows symbolize the donor cell: red- cardiomyocytes, green- cardiac fibroblasts, light brown – endothelial cells, purple – inflammatory cells, and blue – mesenchymal stem cells.

FIGURE 3

Crosstalk between the heart and peripheral organs during cardiac pathological remodeling. Response to cardiac injury is a multi-organ process as it affects not only the heart but also the brain, kidneys, adipose tissue, and the liver, among others. In turn, a variety of other tissues can contribute to cardiac pathological remodeling, not only by secreting specific chemokines but also by releasing exosomal ncRNAs into the blood stream and further affecting cardiac function through intricate signaling networks. Dashed lines represent findings that need further validation.