Increased BACE1-AS Long Noncoding RNA and Β-Amyloid Levels in Heart Failure

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 &bgr;-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 &bgr;-amyloid. In keeping with these findings, higher BACE1 protein and &bgr;-amyloid peptide levels were also observed in HF. Moreover, increased &bgr;-amyloid 1-40 was also found in the plasma of HF patients. Transcriptomic changes of BACE1-AS overexpressing and &bgr;-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 ‘TGF&bgr;-, TNF&agr;-, p38-, EGFR-signalling’, suggesting a potential maladaptive role of the BACE1-AS/BACE1/&bgr;-amyloid axis. Accordingly, the administration of &bgr;-amyloid peptides decreased the cell viability in endothelial cells and in both human IPS-derived and mouse cardiomyocytes. Moreover, both &bgr;-amyloid treatment and BACE1-AS overexpression increased endothelial cell apoptosis, and this effect was prevented by BACE1 silencing. Conclusion Given the neurotoxic role of &bgr;-amyloid in AD, dysregulation of the BACE1/BACE1-AS/&bgr;-amyloid axis might be relevant in HF pathogenesis, further implicating ncRNAs in the complex scenario of proteotoxicity in cardiac dysfunction.