Abstract 14743: BACE1-AS Long Noncoding RNA and beta-amyloid Increase In Ischemic Heart Failure
Introduction: The long noncoding RNA BACE1-AS is transcribed from the opposite strand of the β-secretase (BACE1) gene, coding for a protease generating beta-amyloid peptides from the Amyloid Precursor Protein. Unlike many antisense RNAs that display a negative effect on the sense counterpart, BACE1-AS positively modulates BACE1 expression. Intriguingly, heart failure and Alzheimer’s disease share several effectors and risk factors. Moreover, amyloids originating from a variety of amyloidogenic proteins, can accumulate in the heart and blood vessels and are associated with cardiovascular disorders
Hypothesis: Evaluating if the BACE1-AS/BACE1/beta-amyloid pathway is dysregulated in ischemic heart failure.
Methods and results: BACE1-AS and BACE1 transcripts were both up-regulated in left ventricle biopsies derived from 18 patients affected by non-end stage dilated ischemic cardiomyopathy compared with 17 matched controls. Increased BACE1-AS and BACE1 RNA levels were also observed in mice 1 month after myocardial infarction was induced by coronary artery ligation. In situ hybridization assay in human heart biopsies showed that BACE1-AS RNA displayed an ubiquitous distribution, being expressed in the nucleus of cardiomyocytes, endothelial and fibroblast heart cells. Up- or down-modulation of BACE1-AS levels induced the concordant regulation of BACE1 RNA and protein levels, as well as of beta-amyloid, in cell cultures of both endothelial cells and cardiomyocytes. Accordingly, beta-amyloid protein expression levels were significantly increased in both plasma and left ventricle tissue of heart failure patients. Transcriptomic analysis of cultured endothelial cells where BACE1-AS expression was blocked indicated changes of pathways and functions relevant for cardiovascular ischemic diseases. Accordingly, administration of both beta-amyloid 1-40 and 1-42 peptides induced the cell death of cultured cardiomyocytes and endothelial cells.
Conclusions: Given the toxic role of beta-amyloid, the dysregulation of the BACE1/BACE1-AS axis might be a relevant component of heart failure pathogenesis, further involving noncoding RNAs in the complex scenario of proteotoxicity in cardiac dysfunction.
Author Disclosures: S. Greco: None. G. Zaccagnini: None. P. Fuschi: None. C. Voellenkle: None. S. C astelvecchio: None. L. Menicanti: None. F. Martelli: None.
- © 2016 by American Heart Association, Inc.