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TRNA-derived fragments tRF^GlnCTG induced by arterial injury promote vascular smooth muscle cell proliferation.

ABSTRACT: tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs) are originated from the specific cleavage of endogenous tRNAs or their precursors and regulate gene expression when the cells are in stressful circumstances. Here, we replicated the rat common carotid artery (CCA) intimal hyperplasia model and investigated the expression of tRFs/tiRNAs in the artery. The normal and the balloon-injured rat CCAs were subjected to small RNA sequencing, and then the differentially expressed tRFs/tiRNAs were identified and analyzed. The expression profiles of tRFs/tiRNAs in the healthy and injured CCAs were remarkably different. tRNA^GlnCTG-derived fragments (tRF^GlnCTG) were found to be overexpressed with a high abundance in the injured CCA. In in vitro experiments, the synthetic tRF^GlnCTG mimetics elevated the proliferation and migration of rat vascular smooth muscle cells (VSMCs). Through bioinformatics analysis and an overexpression experiment, tRF^GlnCTG was found to negatively regulate the expression of FAS cell surface death receptor (FAS). This study revealed that tRF^GlnCTG is a crucial regulator in promoting VSMC proliferation. The investigation of the roles of tRFs/tiRNAs is of significance for understanding the mechanism, diagnosis, and treatment of intimal hyperplasia.

SUBMITTER: Zhu XL

PROVIDER: S-EPMC7819823 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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tRNA-derived fragments tRF<sup>GlnCTG</sup> induced by arterial injury promote vascular smooth muscle cell proliferation.

Zhu Xiao-Ling XL Li Tao T Cao Yu Y Yao Qing-Ping QP Liu Xing X Li Ying Y Guan Yang-Yang YY Deng Ji-Jun JJ Jiang Rui R Jiang Jun J

Molecular therapy. Nucleic acids 20201215

tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs) are originated from the specific cleavage of endogenous tRNAs or their precursors and regulate gene expression when the cells are in stressful circumstances. Here, we replicated the rat common carotid artery (CCA) intimal hyperplasia model and investigated the expression of tRFs/tiRNAs in the artery. The normal and the balloon-injured rat CCAs were subjected to small RNA sequencing, and then the differentially expressed tRFs/tiRNAs were iden ...[more]

PMID: 33552681

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Project description:Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis is increased and how increased glycolysis contributes to pulmonary vascular remodeling in PAH.Objectives: To determine whether increased glycolysis is caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and how PFKFB3-driven glycolysis induces vascular remodeling in PAH.Methods: PFKFB3 levels were measured in pulmonary arteries of patients and animals with PAH. Lactate levels were assessed in lungs of animals with PAH and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacologic approaches were used to investigate the role of PFKFB3 in PAH.Measurements and Main Results: Lactate production was elevated in lungs of PAH rodents and in platelet-derived growth factor-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of patients and rodents with PAH, in PASMCs of patients with PAH, and in platelet-derived growth factor-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of extracellular signal-regulated kinase (ERK1/2) and calpain-2, and vascular remodeling in PAH rodent models, and reduced platelet-derived growth factor-induced phosphorylation/activation of ERK1/2 and calpain-2, collagen synthesis and proliferation of PASMCs. ERK1/2 inhibition attenuated phosphorylation/activation of calpain-2, and vascular remodeling in Sugen/hypoxia PAH rats, and reduced lactate-induced phosphorylation/activation of calpain-2, collagen synthesis, and proliferation of PASMCs. Calpain-2 inhibition reduced lactate-induced collagen synthesis and proliferation of PASMCs.Conclusions: Upregulated PFKFB3 mediates collagen synthesis and proliferation of PASMCs, contributing to vascular remodeling in PAH. The mechanism is through the elevation of glycolysis and lactate that results in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2.

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TRNA-derived fragments tRF^GlnCTG induced by arterial injury promote vascular smooth muscle cell proliferation.

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tRNA-derived fragments tRF<sup>GlnCTG</sup> induced by arterial injury promote vascular smooth muscle cell proliferation.

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TRNA-derived fragments tRFGlnCTG induced by arterial injury promote vascular smooth muscle cell proliferation.

Publications

tRNA-derived fragments tRF<sup>GlnCTG</sup> induced by arterial injury promote vascular smooth muscle cell proliferation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

TRNA-derived fragments tRF^GlnCTG induced by arterial injury promote vascular smooth muscle cell proliferation.