Inhibition of ABCA1 protein degradation promotes HDL cholesterol efflux capacity and RCT and reduces atherosclerosis in mice

Clinical and epidemiological studies have shown an inverse relationship between plasma levels of HDL cholesterol or its major apolipoprotein, apoA-I, and cardiovascular disease risk. For example, in the Framingham Heart Study, for every 1% increase in circulating HDL, there was a 2% decrease in the global risk of developing coronary heart disease (1). The direct infusion of reconstituted apoA-I particles reduces atherosclerotic plaque size in humans (2), and the overexpression of apoA-I in mice results in elevated HDL levels and the prevention of plaque progression (3, 4). Therefore, raising HDL cholesterol appears to be an attractive therapeutic strategy for atherosclerosis risk reduction. However, it has been observed that therapies such as CETP inhibitors and niacin (5, 6) that increase HDL level are not sufficient to elucidate HDL’s atheroprotective properties. Alternatively, the cardioprotective potential of HDL may be primarily related to its function, namely to promote reverse cholesterol transport (RCT) from peripheral tissues and cells to the liver. Thus, the synergistic enhancement of HDL function, as well as quantity, may represent a more effective means to harness HDL biology for therapeutic gain (7). The ABCA1 has been identified as the key and rate-limiting transporter facilitating the initial steps of HDL formation and of RCT, with hepatic, intestine, or adipose ABCA1 activity being closely associated with plasma HDL level (8). Increased ABCA1 expression in macrophages would be anticipated to enhance RCT and reduce atherosclerosis risk. Thus, ABCA1 has been identified as an emerging target for new pharmacological agents designed to leverage the cardiovascular protective potential of HDL. It is well-established that liver X receptor (LXR)-induced transcriptional upregulation of ABCA1 promotes HDL formation and RCT (9), and a previous study demonstrated that two oxidized products of probucol inhibit ABCA1 degradation, increase HDL level, and reduce atherosclerosis (10). However, how altering ABCA1 protein degradation impacts HDL function is unknown. In the present study, we determined whether an increase in endogenous ABCA1 expression due to altered posttranslational regulation leads to enhanced HDL function and RCT, and consequently an alleviation of atherosclerosis formation. We did so using a novel agent, triacetyl-3-hydroxyphenyladenosine (IMM-H007), which we formerly observed impacts lipid levels in hyperlipidemic hamsters (11). We discovered that IMM-H007 inhibits intracellular ABCA1 degradation, and that this is related to the suppression of calcium-activated calpain activity. The actions of IMM-H007 on ABCA1 result in greater cell-surface ABCA1 content, increased circulating HDL, enhanced HDL cholesterol efflux capacity, the promotion of ABCA1-mediated RCT, and a reduction in atherosclerotic plaque size in hypercholesterolemic mice. As such, IMM-H007 is a promising lead agent candidate for raising HDL quantity, and likely more importantly, for enhancing HDL function.