Abstract
Ischemic injuries will lead to necrotic tissue damage, and post-ischemia angiogenesis plays critical roles in blood flow restoration and tissue recovery. Recently, several types of small RNAs have been reported to be involved in this process. In this study, we first generated a rat brain ischemic model to investigate the involvement of new types of small RNAs in ischemia. We utilized deep sequencing and bioinformatics analyses to demonstrate that the level of small RNA fragments derived from tRNAs strikingly increased in the ischemic rat brain. Among these sequences, tRNAVal- and tRNAGly-derived small RNAs account for the most abundant segments. The up-regulation of tRNAVal- and tRNAGly-derived fragments was verified through northern blot and quantitative PCR analyses. The levels of these two fragments also increased in a mouse hindlimb ischemia model and cellular hypoxia model. Importantly, up-regulation of the tRNAVal- and tRNAGly-derived fragments in endothelial cells inhibited cell proliferation, migration and tube formation. Furthermore, we showed that these small RNAs are generated by angiogenin cleavage. Our results indicate that tRNA-derived fragments are involved in tissue ischemia, and we demonstrate for the first time that tRNAVal- and tRNAGly-derived fragments inhibit angiogenesis by modulating the function of endothelial cells.
Highlights
Ischemic injuries are due to the interruption of or an insufficient blood supply and can lead to a loss of function in ischemic organs
These results indicated that transfer RNAs (tRNAs) are cleaved into small fragments during ischemia, suggesting that these tRNA-derived fragments may play important roles in brain tissue ischemia
Ischemic stroke is a common clinical disorder and generally causes vascular and neuronal damage, both of which affect the extent of ischemic injury and post-stroke outcome[7]
Summary
Ischemic injuries are due to the interruption of or an insufficient blood supply and can lead to a loss of function in ischemic organs. A recent study published by Yan H and colleagues[13] demonstrated that piRNA-823 can act a positive regulator of neovascularization to promote tumorigenesis This initial evidence for a functional role of piRNAs in angiogenesis implicates the importance of another class of small non-coding RNAs in this process. Subsequent studies showed that various stress conditions can induce tRNA cleavage, and these fragments can serve as small interfering RNAs that regulate the activity of translation factors[22,23,24]. They function as modulators in diverse biological processes, including cell proliferation and apoptosis[19,20,25]. Our results suggest that these tRNA-derived small RNAs function as negative regulators of angiogenesis
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