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Institute
Hofmann, Patrick ; Sommer, Janina ; Theodorou, Kosta ; Kirchhof, Luisa ; Fischer, Ariane ; Li, Yuhuang ; Perisic, Ljubica ; Hedin, Ulf ; Mägdefessel, Lars ; Dimmeler, Stefanie ; Boon, Reinier
Aims: Long non-coding RNAs (lncRNAs) have been shown to regulate numerous processes in the human genome, but the function of these transcripts in vascular aging is largely unknown. We aim to characterize the expression of lncRNAs in endothelial aging and analyse the function of the highly conserved lncRNA H19.
Methods and results: H19 was downregulated in endothelium of aged mice. In human, atherosclerotic plaques H19 was mainly expressed by endothelial cells and H19 was significantly reduced in comparison to healthy carotid artery biopsies. Loss of H19 led to an upregulation of p16 and p21, reduced proliferation and increased senescence in vitro. Depletion of H19 in aortic rings of young mice inhibited sprouting capacity. We generated endothelial-specific inducible H19 deficient mice (H19iEC-KO), resulting in increased systolic blood pressure compared with control littermates (Ctrl). These H19iEC-KO and Ctrl mice were subjected to hindlimb ischaemia, which showed reduced capillary density in H19iEC-KO mice. Mechanistically, exon array analysis revealed an involvement of H19 in IL-6 signalling. Accordingly, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were upregulated upon H19 depletion. A luciferase reporter screen for differential transcription factor activity revealed STAT3 as being induced upon H19 depletion and repressed after H19 overexpression. Furthermore, depletion of H19 increased the phosphorylation of STAT3 at TYR705 and pharmacological inhibition of STAT3 activation abolished the effects of H19 silencing on p21 and vascular cell adhesion molecule 1 expression as well as proliferation.
Conclusion: These data reveal a pivotal role for the lncRNA H19 in controlling endothelial cell aging.
Trembinski, Dorotée Julia ; Bink, Diewertje I. ; Theodorou, Kosta ; Sommer, Janina ; Fischer, Ariane ; Bergen, Anke van ; Kuo, Chao-Chung ; Costa, Ivan G. ; Schürmann, Christoph ; Leisegang, Matthias ; Brandes, Ralf ; Alekseeva, Tijna ; Brill, Boris ; Wietelmann, Astrid ; Johnson, Christopher N. ; Spring-Connell, Alexander ; Kaulich, Manuel ; Werfel, Stanislas ; Engelhardt, Stefan ; Hirt, Marc Nikolaus ; Yorgan, Kaja ; Eschenhagen, Thomas ; Kirchhof, Luisa ; Hofmann, Patrick ; Jaé, Nicolas Christopher ; Wittig, Ilka ; Hamdani, Nazha ; Bischof, Corinne ; Krishnan, Jaya ; Houtkooper, Riekelt H. ; Dimmeler, Stefanie ; Boon, Reinier
Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.
Aamodt, Kenneth ; Abel, N. ; Abeysekara, U. ; Abrahantes Quintana, Arian ; Abramyan, A. ; Adamová, Dagmar ; Aggarwal, Madan Mohan ; Aglieri Rinella, Gianluca ; Agocs, A.G. ; Aguilar Salazar, S. ; Ahammed, Zubayer ; Ahmad, A. ; Ahmad, Nazeer ; Ahn, Sang Un ; Akimoto, R. ; Akindinov, Alexander ; Aleksandrov, Dmitry ; Alessandro, Bruno ; Alfaro Molina, Jose Ruben ; Alici, Andrea ; Almaráz Aviña, E. ; Alme, Johan ; Alt, Torsten ; Altini, V. ; Altinpinar, Sedat ; Andrei, Cristian ; Andronic, Anton ; Anelli, G. ; Angelov, V. ; Anson, Christopher Daniel ; Antičić, Tome ; Antinori, Federico ; Antinori, S. ; Antipin, K. ; Antończyk, Dariusz ; Antonioli, Pietro ; Anzo, A. ; Aphecetche, Laurent Bernard ; Appelshäuser, Harald ; Arcelli, Silvia ; Arceo, R. ; Arend, A. ; Armesto, Néstor ; Arnaldi, Roberta ; Aronsson, Tomas Robert ; Arsene, Ionut Cristian ; Asryan, A. ; Augustinus, Andre ; Averbeck, Ralf Peter ; Awes, T.C. ; Äystö, J. ; Azmi, Mohd Danish ; Bablok, Sebastian ; Bach, Matthias ; Badalà, Angela ; Baek, Yong Wook ; Bagnasco, Stefano ; Bailhache, Raphaëlle ; Bala, Renu ; Baldisseri, Alberto ; Baldit, A. ; Bán, J. ; Barbera, Roberto ; Barnaföldi, Gergely Gábor ; Barnby, L. ; Barret, Valérie ; Bartke, Jerzy ; Barile, Francesco ; Basile, Maurizio ; Basmanov, V. ; Bastid, Nicole ; Bathen, Bastian ; Batigne, Guillaume ; Batyunya, Boris ; Baumann, C. ; Bearden, Ian Gardner ; Becker, B. ; Belikov, Iouri ; Bellwied, Rene ; Belmont-Moreno, Ernesto ; Belogianni, A. ; Benhabib, L. ; Beolè, Stefania ; Berceanu, Ionela ; Bercuci, Alexandru ; Berdermann, E. ; Berdnikov, Yaroslav ; Betev, Latchezar ; Bhasin, Anju ; Bhati, Ashok Kumar ; Bianchi, Livio ; Bianchi, Nicola ; Bianchin, Chiara ; Bielčík, Jaroslav ; Bielčíková, Jana ; Bilandzic, Ante ; Bimbot, L. ; Biolcati, E. ; Blanc, A. ; Blanco, Fernando ; Blanco, Fernando ; Blau, Dmitry S. ; Blume, Christoph ; Boccioli, M. ; Bock, N. ; Bogdanov, Alexey A. ; Bøggild, Hans ; Bogolyubsky, M. ; Bohm, J. ; Boldizsár, László ; Bombara, Marek ; Bombonati, C. ; Bondila, M. ; Borel, Hervé ; Borisov, A. ; Bortolin, C. ; Bose, S. ; Bosisio, L. ; Bossú, Francesco ; Botje, Michiel ; Böttger, Stefan ; Bourdaud, G. ; Boyer, B. ; Braun, M. ; Braun-Munzinger, Peter ; Bravina, L. ; Bregant, Marco ; Breitner, Timo ; Bruckner, G. ; Brun, René ; Bruna, Elena ; Bruno, Giuseppe Eugenio ; Budnikov, Dmitry ; Büsching, Henner ; Bunčić, Predrag ; Busch, Oliver ; Buthelezi, Edith Zinhle ; Caffarri, Davide ; Cai, Xiao ; Caines, Helen Louise ; Calvo, E. ; Camacho, E. ; Camerini, Paolo ; Campbell, M. ; Canoa Roman, Veronica ; Capitani, G.P. ; Cara Romeo, G. ; Carena, Francesco ; Carena, Wisla ; Carminati, F. ; Casanova Díaz, A. ; Caselle, M. ; Castillo Castellanos, Javier Ernesto ; Castillo Hernandez, Juan Francisco ; Catanescu, V. ; Cattaruzza, E. ; Cavicchioli, Costanza ; Cerello, Piergiorgio ; Chambert, V. ; Chang, B. ; Chapeland, Sylvain ; Charpy, A. ; Charvet, Jean-Luc Fernand ; Chattopadhyay, S. ; Chattopadhyay, S. ; Cherney, Michael Gerard ; Cheshkov, Cvetan Valeriev ; Cheynis, Brigitte ; Chiavassa, E. ; Chibante Barroso, Vasco Miguel ; Chinellato, David Dobrigkeit ; Chochula, Peter ; Choi, Kyungeon ; Chojnacki, Marek ; Christakoglou, Panagiotis ; Christensen, Christian Holm ; Christiansen, Peter L. ; Chujo, Tatsuya ; Chuman, F. ; Cicalò, Corrado ; Cifarelli, Luisa ; Cindolo, Federico ; Cleymans, Jean Willy Andre ; Cobanoglu, O. ; Coffin, J.-P. ; Coli, S. ; Colla, A. ; Conesa Balbastre, Gustavo ; Conesa del Valle, Zaida ; Conner, E.S. ; Constantin, P. ; Contin, Giacomo ; Contreras Nuno, Jesus Guillermo ; Corrales Morales, Yasser ; Cormier, Thomas Michael ; Cortese, Pietro ; Cortés Maldonado, Ismael ; Cosentino, Mauro Rogerio ; Costa, Filippo ; Cotallo, M.E. ; Crescio, E. ; Crochet, Philippe ; Cuautle Flores, Eleazar ; Cunqueiro Mendez, Leticia ; Cussonneau, J. ; Dainese, Andrea ; Dalsgaard, H.H. ; Danu, Andrea ; Das, Indranil ; Dash, Ajay Kumar ; Dash, Sadhana ; de Barros, G.O.V. ; De Caro, Annalisa ; De Cataldo, Giacinto ; Cuveland, Jan de ; De Falco, Alessandro ; 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The inclusive charged particle transverse momentum distribution is measured in proton–proton collisions at s=900 GeV at the LHC using the ALICE detector. The measurement is performed in the central pseudorapidity region (|η|<0.8) over the transverse momentum range 0.15<pT<10 GeV/c. The correlation between transverse momentum and particle multiplicity is also studied. Results are presented for inelastic (INEL) and non-single-diffractive (NSD) events. The average transverse momentum for |η|<0.8 is 〈pT〉INEL=0.483±0.001 (stat.)±0.007 (syst.) GeV/c and 〈pT〉NSD=0.489±0.001 (stat.)±0.007 (syst.) GeV/c, respectively. The data exhibit a slightly larger 〈pT〉 than measurements in wider pseudorapidity intervals. The results are compared to simulations with the Monte Carlo event generators PYTHIA and PHOJET.
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