title: The mitochondrial lncRNA ASncmtRNA-2 is induced in aging and replicative senescence in Endothelial Cells.
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.
authors: Unità di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino (CCM), IRCCS, Milano, Italy.
authors: Valentina
authors: V
authors: Bianchessi
authors: Unità di Cardio-Oncologia Sperimentale e Invecchiamento Cardiovascolare, Centro Cardiologico Monzino (CCM), IRCCS, Milano, Italy.
authors: Ileana
authors: I
authors: Badi
authors: Unità di Cardio-Oncologia Sperimentale e Invecchiamento Cardiovascolare, Centro Cardiologico Monzino (CCM), IRCCS, Milano, Italy.
authors: Matteo
authors: M
authors: Bertolotti
authors: Unità di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino (CCM), IRCCS, Milano, Italy.
authors: Patrizia
authors: P
authors: Nigro
authors: Unità di Immunologia e Genomica Funzionale, Centro Cardiologico Monzino (CCM), IRCCS, Milano, Italy.
authors: Yuri
authors: Y
authors: D'Alessandra
authors: Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata (IDI), IRCCS, Roma, Italy.
authors: Maurizio C
authors: MC
authors: Capogrossi
authors: Dipartimento di Chirurgia Vascolare, Centro Cardiologico Monzino (CCM), IRCCS, Milano, Italy.
authors: Marco
authors: M
authors: Zanobini
authors: Unità di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino (CCM), IRCCS, Milano, Italy.
authors: Giulio
authors: G
authors: Pompilio
authors: Unità di Cardio-Oncologia Sperimentale e Invecchiamento Cardiovascolare, Centro Cardiologico Monzino (CCM), IRCCS, Milano, Italy.
authors: Angela
authors: A
authors: Raucci
authors: Unità di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino (CCM), IRCCS, Milano, Italy. Electronic address: alauri@ccfm.it.
authors: Andrea
authors: A
authors: Lauri
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001483:Base Sequence; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D000077278:RNA, Mitochondrial; D015398:Signal Transduction; D014466:Ultraviolet Rays
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D000077278:RNA, Mitochondrial; D012313:RNA; D006861:Hydrogen Peroxide
keywords: Endothelial cells; Mitochondria; Senescence; Vascular aging; lncRNA; miRNA