Regulation of microvascularization in heart failure - an endothelial cell, non-coding RNAs and exosome liaison

Abstract

Heart failure is a complex syndrome involving various pathophysiological processes. An increasing body of evidence shows that the myocardial microvasculature is essential for the homeostasis state and that a decompensated heart is associated with microvascular dysfunction as a result of impaired endothelial angiogenic capacity. The intercellular communication between endothelial cells and cardiomyocytes through various signaling molecules, such as vascular endothelial growth factor, nitric oxide, and non-coding RNAs is an important determinant of cardiac microvascular function. Non-coding RNAs are transported from endothelial cells to cardiomyocytes, and vice versa, regulating microvascular properties and angiogenic processes in the heart. Small-exocytosed vesicles, called exosomes, which are secreted by both cell types, can mediate this intercellular communication. The purpose of this review is to highlight the contribution of the microvasculature to proper heart function maintenance by focusing on the interaction between cardiac endothelial cells and myocytes with a specific emphasis on non-coding RNAs (ncRNAs) in this form of cell-to-cell communication. Finally, the potential of ncRNAs as targets for angiogenesis therapy will also be discussed.

CAD increases the long noncoding RNA PUNISHER in small extracellular vesicles and regulates endothelial cell function via vesicular shuttling

“…There was no significant difference in PUNISHER expression levels between the two groups (Figure S2D), confirming the stability of ncRNAs in frozen plasma over several years, if stored correctly. 45 Atherosclerotic stimuli cause endothelial sEV to be enriched in PUNISHER in vitro Because we found that sEVs containing PUNISHER were significantly upregulated in patients with CAD, and previous studies show that PUNISHER is an endothelial-specific lncRNA, 41,46 we next explored whether pro-atherosclerotic conditions might regulate cellular or sEV-incorporated PUNISHER expression levels in vitro. First, ECderived sEVs were isolated from human coronary artery ECs (HCAECs) through a series of differential ultracentrifugation steps, as previously described (Figure S2A).…”

Therapeutic vascular growth in the heart

“…Currently, in response to poor cell engraftment observed with cell therapy, the field is turning toward the use of cell-free alternatives in the form of exosomes or microvesicles as a shelfable source of regenerative benefit including, but not limited to, stimulation of angiogenesis. These extracellular vesicles (EVs), shedded by cardiac stem cells or by embryonic or induced pluripotent stem cell (iPS)-derived cardiomyocytes, act, following endocytosis, to release intracellularly various angiogenic regulators including transcription factors, growth factors, bioactive lipids, as well as epigenetic regulators such as microRNA (miR) and long-noncoding RNA that together may better orchestrate tissue repair and regeneration (46,47,48,49). The first phase I clinical trial with exosomes for ischemia, aiming at stimulation of angiogenesis as well as modulation of inflammation, is set to start in 2019 in patients with ischemic stroke (clinicaltrials.gov/NCT03384433).…”

Induction of cardiomyocyte proliferation, a new way forward for true myocardial regeneration?

“…miRNAs regulate the expression of a target mRNA by binding to the 3'UTR and hereby either preventing the translation of the mRNA or aiding in its degradation. LncRNAs (>200 nucleotides) can regulate epigenetic gene silencing, bind to miRNAs, and function as protein scaffolds (22). Exploring the expression at P1, P3, P5, P7, and P10 showed differential expression of the 413 miRNAs and 545 lncRNAs in both endothelial cells and cardiomyocytes (23).…”