AMYLOID BETA 1–40 AND ITS UPSTREAM REGULATORY PATHWAY BACE1-AS LONG NONCODING RNA/BACE1 ARE ASSOCIATED WITH PRESENCE AND SEVERITY OF HUMAN ATHEROSCLEROTIC DISEASE

Abstract

Objective: Amyloid-beta (1–40) (Ab40), is associated with accelerated atherosclerosis and adverse cardiac events. Ab40 production is mainly dependent on the cleavage of amyloid precursor protein by beta-amyloid cleaving enzyme-1 (BACE1). BACE1 antisense (BACE1-AS) is a long-noncoding RNA that enhances BACE1 stability. The objective of this study is to evaluate the clinical value of plasma amyloid-beta levels and its upstream regulatory pathway BACE1/BACE1-AS in patients with subclinical and established cardiovascular disease. Design and method: Plasma levels of Ab40 were measured in 642 consecutively recruited patients with and without coronary artery disease (CAD). BACE1-AS lncRNA and BACE1 mRNA expression were measured in peripheral blood mononuclear cells from 214 study participants. Intima-media thickness and atheromatous plaques by ultrasonography, arterial wave reflections and pulse wave velocity were used as surrogate markers of subclinical CVD. The burden of cardiovascular risk factors (CVRFs) included impaired glomerular filtration rate (<60 ml/min), smoking, hypertension, hyperlipidemia, diabetes, obesity and increased hsCRP. Results: Both in non-CAD (n = 369) and CAD (n = 273) patients, Ab40 was associated with age, aortic and peripheral systolic and pulse pressure, and low GFR (p < 0.05 for all). In non-CAD subjects, Ab40 also correlated with diabetes and low HDL. Importantly, Ab40 was associated with the presence of any plaque in non-CAD subjects (p = 0.035) and with increased number of diseased coronary arteries (p = 0.022) independently of age, gender and CVRFs. Ab40 plasma levels were increased in the highest tertile of BACE/BACE1AS (p < 0.05) while their levels were highly intercorrelated (r = 0.825, P < 0.001). BACE1/BACE1-AS levels progressively increased across the 3 groups of non-CAD (n = 145), stable-CAD (n = 43) and acute myocardial infarction (n = 26) patients (p for trend < 0.001). Among non-CAD subjects, both BACE1/BACE1-AS were increased in individuals with >2 CVRFs. Among CAD patients, BACE1-AS was associated with decreased LVEF (<50%) (adjusted OR = 1.92 per 1-SD increase, p = 0.047) while BACE1 in the highest tertile was associated with 5-fold higher odds for coronary multi-vessel disease (p = 0.004). Conclusions: Circulating Ab40 and increased expression of its upstream regulators BACE1/BACE1-AS are intercorrelated and associated with the presence and severity of atherosclerosis. BACE1-AS/BACE1-mediated increased availability of Ab40 may play a pivotal role in its adverse cardiovascular effects.