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Age-associated cardiovascular diseases are at least partially ascribable to vascular cell senescence. Replicative senescence (RS) and stress-induced premature senescence (SIPS) are provoked respectively by endogenous (telomere erosion) and exogenous (H2O2, UV) stimuli resulting in cell cycle arrest in G1 and G2 phases. In both scenarios, mitochondria-derived ROS are important players in senescence initiation. We aimed to define whether a mtDNA-transcribed long-non-coding-RNA (lncRNA), ASncmtRNA-2, has a role in vascular aging and senescence. Aortas of old mice, characterized by increased senescence, showed an increment in ASncmtRNA-2 expression. In vitro analysis of Endothelial Cells (EC) and Vascular Smooth Muscle Cells (VSMC) established that ASncmtRNA-2 is induced in EC, but not in VSMC, during RS. Surprisingly, ASncmtRNA-2 is not upregulated in two different EC SIPS scenarios, treated with H2O2 and UV. The p16 gene displayed similar ASncmtRNA-2 expression patterns, suggesting a possible co-regulation of the two genes. Interestingly, the expression of two miRNAs, hsa-miR-4485 and hsa-miR-1973, with perfect homology to the double strand region of ASncmtRNA-2 and originating at least in part from a mitochondrial transcript, was induced in RS, opening to the possibility that this lncRNA functions as a non-canonical precursor of these miRNAs. Cell cycle analysis of EC transiently over-expressing ASncmtRNA-2 revealed an accumulation of EC in the G2/M phase, but not in the G1 phase. We propose that ASncmtRNA-2 in EC might be involved in the RS establishment by participating in the cell cycle arrest in G2/M phase, possibly through the production of hsa-miR-4485 and hsa-miR-1973. This article is part of a Special Issue entitled: Mitochondria.

Original publication

DOI

10.1016/j.yjmcc.2015.01.012

Type

Journal article

Journal

J Mol Cell Cardiol

Publication Date

04/2015

Volume

81

Pages

62 - 70

Keywords

Endothelial cells, Mitochondria, Senescence, Vascular aging, lncRNA, miRNA, Aging, Animals, Aorta, Base Sequence, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, G2 Phase Cell Cycle Checkpoints, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells, Humans, Hydrogen Peroxide, Male, Mice, Mice, Inbred C57BL, MicroRNAs, Mitochondria, Molecular Sequence Data, Myocytes, Smooth Muscle, RNA, RNA, Long Noncoding, RNA, Mitochondrial, Signal Transduction, Ultraviolet Rays