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  • The differential tissue and ligand dependent signaling descr

    2021-09-10

    The differential tissue- and ligand-dependent signaling described here has important implications for the therapeutic potential of synthetic GPR109A agonists for the treatment of atherosclerosis. The failure of MK-0354, a biased, partial GPR109A agonist, to activate signaling pathways upstream of vasodilatory prostanoid release in Langerhans Triciribine sale provides a direct mechanistic basis for the compound's inability to produce a flushing response. In the present study, MK-0354 also failed to initiate significant functional responses in macrophages which are likely to be involved in anti-atherogenic action in macrophages. Additionally, MK-0354 had no effect on RANTES signaling, and thus may not interfere with macrophage recruitment to the plaque. Indeed, MK-0354 behaved as a functional antagonist of niacin-mediated GPR109A signaling in macrophages, raising the possibility that it may interfere with the potential anti-atherogenic activity of any endogenous GPR109A ligand(s). These data strongly suggest that it may be impossible to separate the cutaneous flushing side effects of GPR109A agonists from their potential therapeutic effects mediated through macrophages and other immune cells (Fig. 8B). Results of recent clinical studies and developments in the field of atherosclerotic disease raise significant questions about the hypotheses underlying previous clinical evaluations of GPR109A agonists and may necessitate a reevaluation of the types of endpoints employed in future clinical studies. As the Coronary Drug Project demonstrated, niacin is undoubtedly efficacious in ameliorating cardiovascular disease, yielding reductions in cardiovascular morbidities, including myocardial infarction, stroke, and the need for coronary bypass surgery. Niacin-induced elevations of HDL and beneficial changes in broader lipid profiles appear to be produced via an unclear, but GPR109A-independent mechanism. However, as suggested by recent clinical studies of CETP inhibitors, the elevation of HDL by itself may not lead to clinically meaningful benefit [32]. The efficacy endpoints employed in recent clinical studies of GPR109A agonists were based upon the ability of niacin to modify plasma lipid profiles, in particular elevation of HDL, a mode of action that now appears to be independent of GPR109A. The failure of test compounds to modify lipid profiles led to discontinuation of their clinical evaluation. However, since GPR109A agonists may possess immune cell GPR109A-mediated anti-atherosclerotic activity, the use of the more disease-relevant diagnostic criteria, such as carotid artery intima-media thickness might provide for a more informative evaluation of potential clinical benefit. Based on data presented in the current study, it is unlikely that MK-0354 or compounds with a similar, biased signaling profile will provide immune cell mediated beneficial effects on atherosclerosis. Compounds with niacin-like signaling properties in macrophages, such as MK-1903, are likely to provide niacin-like beneficial effects mediated by immune cells, but will most likely retain the undesirable flushing side effect and offer few advantages over niacin itself. The identification of a GPCR expressed on macrophages, possessing GPR109A-like signaling properties but lacking expression on Langerhans cells and keratinocytes that mediate the flushing response, might provide a more attractive target for the investigation of immune cell mediated anti-atherosclerotic potential. Interestingly, in the recent AIM-HIGH trial, administration of niacin on top of statin therapy failed to yield additional clinical benefit in patients with very low LDL-c background [38]. A potential explanation for this disappointing and unexpected result may be that lowering of LDL-c depletes atherosclerotic plaques of their lipid core to such an extent that any contribution of niacin mediated mechanisms to modulating the plaque becomes relatively insignificant. However, the final verdict on clinical potential of niacin as a statin-combination therapy is still outstanding, since the AIM-HIGH study had numerous limitations [39], [40]. In particular, subjects in the control arm of the study received niacin at doses sufficient to elicit a flushing response, but much lower than those required to have an effect on HDL. Thus, the absence of an additional clinical benefit from niacin may have been due to niacin exerting its immune cell mediated anti-atherogenic activity in both arms of the study.