The mitochondrial lncRNA ASncmtRNA-2 is induced in aging and replicative senescence in Endothelial Cells

J Mol Cell Cardiol. 2015 Apr;81:62-70. doi: 10.1016/j.yjmcc.2015.01.012. Epub 2015 Jan 29.

Abstract

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.

Keywords: Endothelial cells; Mitochondria; Senescence; Vascular aging; lncRNA; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Aorta / cytology
  • Aorta / metabolism
  • Base Sequence
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • G2 Phase Cell Cycle Checkpoints / radiation effects
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells / radiation effects
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Molecular Sequence Data
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / radiation effects
  • RNA / genetics*
  • RNA / metabolism
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA, Mitochondrial
  • Signal Transduction
  • Ultraviolet Rays

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • MicroRNAs
  • RNA, Long Noncoding
  • RNA, Mitochondrial
  • RNA
  • Hydrogen Peroxide