Role of adenylate cyclase 9 in the pharmacogenomic response to dalcetrapib clinical paradigm and molecular mechanisms in precision cardiovascular medicine

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.Cardiolog

CETP Deficiency and Concerns in CETP Inhibitor Development

Although some CETP-lowering SNPs in the CETP gene are variably associated with improved clinical outcomes in patients with coronary artery disease (CAD), three low molecular weight oral CETP inhibitors (torcetrapib, dalcetrapib, and evacetrapib) have not shown any clinical benefits despite remarkable increases in HDL-cholesterol levels ranging 31-138%. Potential causes for that failure are discussed in terms of off-target effects of some inhibitors, potential misleading interpretation of genetic epidemiological surveys in CETP gene, and inadequate alteration in HDL function induced by the inhibitors. Possible modalities of CETP inhibition such as antisense nucleotides and monoclonal antibodies are discussed.A part of the boo

Will Lipidation of ApoA1 through Interaction with ABCA1 at the Intestinal Level Affect the Protective Functions of HDL?

The relationship between levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular (CV) risk is well recognized; however, in recent years, large-scale phase III studies with HDL-C-raising or -mimicking agents have failed to demonstrate a clinical benefit on CV outcomes associated with raising HDL-C, casting doubt on the “HDL hypothesis.” This article reviews potential reasons for the observed negative findings with these pharmaceutical compounds, focusing on the paucity of translational models and relevant biomarkers related to HDL metabolism that may have confounded understanding of in vivo mechanisms. A unique function of HDL is its ability to interact with the ATP-binding cassette transporter (ABC) A1 via apolipoprotein (Apo) A1. Only recently, studies have shown that this process may be involved in the intestinal uptake of dietary sterols and antioxidants (vitamin E, lutein and zeaxanthin) at the basolateral surface of enterocytes. This parameter should be assessed for HDL-raising drugs in addition to the more documented reverse cholesterol transport (RCT) from peripheral tissues to the liver. Indeed, a single mechanism involving the same interaction between ApoA1 and ABCA1 may encompass two HDL functions previously considered as separate: antioxidant through the intestinal uptake of antioxidants and RCT through cholesterol efflux from loaded cells such as macrophages

HDL as Bidirectional Lipid Vectors: Time for New Paradigms

The anti-atherogenic properties of high-density lipoproteins (HDL) have been explained mainly by reverse cholesterol transport (RCT) from peripheral tissues to the liver. The RCT seems to agree with most of the negative epidemiological correlations between HDL cholesterol levels and coronary artery disease. However, therapies designed to increase HDL cholesterol failed to reduce cardiovascular risk, despite their capacity to improve cholesterol efflux, the first stage of RCT. Therefore, the cardioprotective role of HDL may not be explained by RCT, and it is time for new paradigms about the physiological function of these lipoproteins. It should be considered that the main HDL apolipoprotein, apo AI, has been highly conserved throughout evolution. Consequently, these lipoproteins play an essential physiological role beyond their capacity to protect against atherosclerosis. We propose HDL as bidirectional lipid vectors carrying lipids from and to tissues according to their local context. Lipid influx mediated by HDL appears to be particularly important for tissue repair right on site where the damage occurs, including arteries during the first stages of atherosclerosis. In contrast, the HDL-lipid efflux is relevant for secretory cells where the fusion of intracellular vesicles drastically enlarges the cytoplasmic membrane with the potential consequence of impairment of cell function. In such circumstances, HDL could deliver some functional lipids and pick up not only cholesterol but an integral part of the membrane in excess, restoring the viability of the secretory cells. This hypothesis is congruent with the beneficial effects of HDL against atherosclerosis as well as with their capacity to induce insulin secretion and merits experimental exploration

SKF 99085 a novel hypocholesterolemic agent with multiple anti-atherosclerotic properties, suppresses HMG-CoA reductase and induces LDL receptor activity by a novel mechanism

Poster abstractPeer reviewe

Perturbation of hormone storage and release induced by cyproheptadine in rat pancreatic islets in vitro

The effects of cyproheptadine (CPH) added in vitro were studied in rat pancreatic islets maintained in culture medium. CPH added over 6 days resulted in either an increase (5 X 10(-7) M CPH) or a marked, but reversible decrease (5 X 10(-5 M) in insulin content of islets when related to that of controls. At both concentrations, however, total recoverable insulin from islets, cells detached from islets, and medium was decreased relative to control cultures. The increased insulin content observed after 6 days with 5 X 10(-7) M CPH may be explained by the partial inhibition of insulin release, preventing the normally occurring early drop in insulin content of control islets. The decreased total recoverable insulin in the culture system with 5 X 10(-5) M CPH (17% of the initial insulin content of the islets placed into the CPH-containing culture medium) was not acounted for by the combined effects of insulin degradation in the culture medium and inhibition of insulin biosynthesis. Together and by exclusion these data suggest increased insulin degradation within beta-cells as a result of exposure to 5 X 10(-5) M CPH. Since increased intracellular insulin degradation was not found at 5 X 10(-7) M CPH, the data suggest that only severe inhibition of insulin release (5 X 10(-5) M CPH) increases intracellular insulin degradation. CPH added in vitro irreversibly decreased islet glucagon content; the data suggest that these effects are due to alterations in the physical properties of the peripheral cell layers of isolated islets. Studies with 5 X 10(-5) M CPH on the biosynthesis of insulin immunoreactive material failed to link the appearance of flocculent material in dilated cisternae of the rough endoplasmic reticulum (observed by electron microscopy) with accumulation of an immunoreactive biosynthetic precursor for insulin

Effects of Niacin Extended-Release and Fenofibrate on Endothelial Function

Aim: Niacin and fenofibrate are to date the most effective available HDL-C raising therapies. We examined the effects of niacin extended-release (ER) and fenofibrate treatment on endothelial function. Methods: In a multicenter, randomized, open-label, cross-over study, dyslipidemic subjects were included; 24 with low HDL-C (<40 mg/dL) and 42 with normal HDL-C (40-59 mg/dL) at baseline, received 6 weeks\u2019 treatment with niacin ER (0.5 g/d then 1 g/d) and fenofibrate (160 mg/d) with 4 weeks\u2019 wash-out between treatments. Lipoprotein composition and particle size distribution were determined using NMR. Endothelial function was assessed by ultrasound brachial flow mediated dilatation (FMD) at start and end of the 6 week treatment periods. Between treatment effects were compared using ANCOVA. In slope analyses within treatments, each of the lipids and lipoproteins were correlated with %FMD, both at baseline and at end of treatment Results: Complete FMD datasets of 19 niacin ER and 17 fenofibrate treatments were available. There was no difference in FMD between treatments (p>0.2). The slope analyses, however, showed correlations between lipids and FMD, the strongest correlations occurred in the niacin ER group. In particular HDL-C (p=0.032), HDL particle size (p=0.009) and LDL sizes correlated with FMD upon niacin ER treatment. Conclusions: There were no differential effects between niacin ER and fenofibrate on endothelial function, however slope analyses revealed lipid modification by niacin ER and (to a lesser extent) fenofibrate can favorably improve endothelial function