Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice.

AIMS: The mechanisms underlying ageing-induced vascular remodelling remain unclear. This study investigates the role and underlying mechanisms of the cytoplasmic deacetylase sirtuin 2 (SIRT2) in ageing-induced vascular remodelling. METHODS AND RESULTS: Transcriptome and quantitative real-time PCR data were used to analyse sirtuin expression. Young and old wild-type and Sirt2 knockout mice were used to explore vascular function and pathological remodelling. RNA-seq, histochemical staining, and biochemical assays were used to evaluate the effects of Sirt2 knockout on the vascular transcriptome and pathological remodelling and explore the underlying biochemical mechanisms. Among the sirtuins, SIRT2 had the highest levels in human and mouse aortas. Sirtuin 2 activity was reduced in aged aortas, and loss of SIRT2 accelerated vascular ageing. In old mice, SIRT2 deficiency aggravated ageing-induced arterial stiffness and constriction-relaxation dysfunction, accompanied by aortic remodelling (thickened vascular medial layers, breakage of elastin fibres, collagen deposition, and inflammation). Transcriptome and biochemical analyses revealed that the ageing-controlling protein p66Shc and metabolism of mitochondrial reactive oxygen species (mROS) contributed to SIRT2 function in vascular ageing. Sirtuin 2 repressed p66Shc activation and mROS production by deacetylating p66Shc at lysine 81. Elimination of reactive oxygen species by MnTBAP repressed the SIRT2 deficiency-mediated aggravation of vascular remodelling and dysfunction in angiotensin II-challenged and aged mice. The SIRT2 coexpression module in aortas was reduced with ageing across species and was a significant predictor of age-related aortic diseases in humans. CONCLUSION: The deacetylase SIRT2 is a response to ageing that delays vascular ageing, and the cytoplasm-mitochondria axis (SIRT2-p66Shc-mROS) is important for vascular ageing. Therefore, SIRT2 may serve as a potential therapeutic target for vascular rejuvenation.

DDX17 modulates the expression and alternative splicing of genes involved in apoptosis and proliferation in lung adenocarcinoma cells.

Background: The DEAD-box RNA-binding protein (RBP) DDX17 has been found to be involved in the tumorigenesis of many types of cancers. However, the role of DDX17 in lung adenocarcinoma (LUAD) remains unclear. Methods: We silenced DDX17 expression in A549 LUAD cells by small interfering RNA (siRNA). Cell proliferation and apoptosis assays were performed to explore the functions of DDX17. Knockdown of DDX17 by siRNA significantly inhibited proliferation and induced apoptosis in A549 cells. We used high-throughput RNA sequencing (RNA-seq) to identify differentially expressed genes (DEGs) and alternative splicing (AS) events in DDX17 knockdown LUAD cells. Results: DDX17 knockdown increased the expression levels of proapoptotic genes and decreased those of proproliferative genes. Moreover, the DDX17-regulated AS events in A549 cells revealed by computational analysis using ABLas software were strongly validated by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and were also validated by analysis of The Cancer Genome Atlas (TCGA)-LUAD dataset. These findings suggest that DDX17 may function as an oncogene by regulating both the expression and AS of proliferation- and apoptosis-associated genes in LUAD cells. Our findings may offer new insights into understanding the molecular mechanisms of LUAD and provide a new therapeutic direction for LUAD.