Increased BACE1-AS long noncoding RNA and β-amyloid levels in heart failure.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Via Morandi, 30 20097 San Donato, Milanese, Milan, Italy.
Simona
S
Greco
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Via Morandi, 30 20097 San Donato, Milanese, Milan, Italy.
Germana
G
Zaccagnini
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Via Morandi, 30 20097 San Donato, Milanese, Milan, Italy.
Paola
P
Fuschi
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Via Morandi, 30 20097 San Donato, Milanese, Milan, Italy.
Christine
C
Voellenkle
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Via Morandi, 30 20097 San Donato, Milanese, Milan, Italy.
Matteo
M
Carrara
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Via Morandi, 30 20097 San Donato, Milanese, Milan, Italy.
Iman
I
Sadeghi
Institute of Cell Biology and Neurobiology (IBCN), National Research Council of Italy (CNR), Monterotondo Scalo, Rome, Italy.
Claudia
C
Bearzi
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Via Morandi, 30 20097 San Donato, Milanese, Milan, Italy.
Biagina
B
Maimone
Department of Cardiac Surgery, IRCCS Policlinico San Donato, Milan, Italy.
Serenella
S
Castelvecchio
Laboratory of RNA Metabolism and Vascular Inflammation, Institute of Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University Frankfurt, Frankfurt/Main, Germany.
Konstantinos
K
Stellos
Division of Cardiovascular Epigenetics, Department of Cardiology and Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt/Main, Germany.
Carlo
C
Gaetano
Department of Cardiac Surgery, IRCCS Policlinico San Donato, Milan, Italy.
Lorenzo
L
Menicanti
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Via Morandi, 30 20097 San Donato, Milanese, Milan, Italy.
Fabio
F
Martelli
D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D014162:Transfection; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; C561565:BACE1-AS long non-coding RNA, human; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; C000623210:long non-coding RNA BACE1-AS, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse
Amyloid; BACE1; BACE1-AS; Heart failure; Long noncoding RNA