The multifaceted roles of non-coding RNAs in cell-cell communication in cardiovascular health and disease.

Non-coding RNAs are critical regulators of cell-to-cell communication in the cardiovascular system, playing pivotal roles in heart development, function, and disease progression. Among these, extracellular vesicles, RNA-binding proteins, and lipoprotein complexes have emerged as key carriers, facilitating the paracrine-and occasionally endocrine-transfer of non-coding RNAs. While extensive evidence supports the role of microRNAs in mediating communication between cardiomyocytes, fibroblasts, endothelial cells, and immune cells, the involvement of long non-coding RNAs and their carriers in cardiac intercellular signaling remains understudied. This review explores how non-coding RNA carriers protect these molecules from extracellular degradation and ensure targeted delivery to recipient cells, enabling precise modulation of gene expression. Furthermore, we highlight the gaps in understanding the mechanisms of non-coding RNA uptake and their implications, which can be addressed through advanced sequencing technologies, such as single-cell RNA sequencing. These tools provide unparalleled insights into non-coding RNA-mediated communication networks in the heart, shedding light on their roles in maintaining homeostasis and driving disease. Finally, we contrast the well-established microRNA-driven communication mechanisms with the emerging significance of long non-coding RNAs. We also discuss how sequencing advancements transform our understanding of non-coding RNA-based signaling pathways in cardiovascular health and disease.