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Lookup NU author(s): Professor Konstantinos StellosORCiD
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© 2017 The Author.Aims Antisense long noncoding RNAs (ncRNAs) are transcripts emerging from the opposite strand of a coding-RNA region and their role in heart failure (HF) is largely unknown. Additionally, HF and Alzheimer's disease (AD) share several non-genetic effectors and risk factors. We investigated the regulation of the β-secretase-1 (BACE1) gene and of its antisense transcript BACE1-AS in ischaemic HF. Methods and results BACE1 and BACE1-AS expression was measured in left ventricle biopsies from 18 patients affected by non-end stage ischaemic HF and 17 matched controls. The levels of both transcripts were increased in HF patients. Likewise, both transcripts increased also in a mouse model of ischaemic HF, and their expression was directly correlated. BACE1-AS was expressed by all cardiac cell types and BACE1-AS up- or down-modulation in cultured cardiomyocytes and endothelial cells induced a concordant regulation of the cognate BACE1 transcript. Interestingly, BACE1 increase also induced the intracellular accumulation of its product β-amyloid. In keeping with these findings, higher BACE1 protein and β-amyloid peptide levels were also observed in HF. Moreover, increased β-amyloid 1-40 was also found in the plasma of HF patients. Transcriptomic changes of BACE1-AS overexpressing and β-amyloid 1-40 treated cells were largely overlapping and indicated changes of relevant biological process such as 'cell cycle and proliferation', 'apoptosis', and 'DNA repair' as well as 'TGFβ-, TNFα-, p38-, EGFR-signalling', suggesting a potential maladaptive role of the BACE1-AS/BACE1/β-amyloid axis. Accordingly, the administration of β-amyloid peptides decreased the cell viability in endothelial cells and in both human IPS-derived and mouse cardiomyocytes. Moreover, both β-amyloid treatment and BACE1-AS overexpression increased endothelial cell apoptosis, and this effect was prevented by BACE1 silencing. Conclusion Given the neurotoxic role of β-amyloid in AD, dysregulation of the BACE1/BACE1-AS/β-amyloid axis might be relevant in HF pathogenesis, further implicating ncRNAs in the complex scenario of proteotoxicity in cardiac dysfunction.
Author(s): Greco S, Zaccagnini G, Fuschi P, Voellenkle C, Carrara M, Sadeghi I, Bearzi C, Maimone B, Castelvecchio S, Stellos K, Gaetano C, Menicanti L, Martelli F
Publication type: Article
Publication status: Published
Journal: Cardiovascular Research
Year: 2017
Volume: 113
Issue: 5
Pages: 453-463
Print publication date: 01/04/2017
Online publication date: 23/02/2017
Acceptance date: 25/01/2017
ISSN (print): 0008-6363
ISSN (electronic): 1755-3245
Publisher: Oxford University Press
URL: https://doi.org/10.1093/cvr/cvx013
DOI: 10.1093/cvr/cvx013
PubMed id: 28158647
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