Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide

Abstract

Aims Chronic adventitial and medial infiltration of immune cells plays an important role in the pathogenesis of abdominal aortic aneurysms (AAA). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation. Methods and Results Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation. Conclusions Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA. Translational perspective AAA are associated with pronounced adventitial and medial inflammation leading to matrix degradation and progressive aortic expansion. We report that niacin blunts aortic inflammation and matrix degradation, thereby suppressing AAA formation. These effects are independent of the niacin receptor GPR109A and mimicked by nicotinamide, which does not induce flushing. These results suggest that nicotinamide and related biomolecules that replete cellular NAD+ may be an effective medical therapy for AAA.

Progress in aorta and peripheral cardiovascular disease research

“…An experimental study in mice indicates now that niacin could prevent abdominal aortic aneurysm (AAA) development independent of GPR109A. 4 The authors show that niacin markedly blunted AAA formation in two mouse models (angiotensin II and CaCl 2 ) with lowered inflammatory responses and matrix degradation. Importantly, deletion of GPR109A gene did not prevent the protective effects.…”

The Role of Sirtuin-1 in the Vasculature: Focus on Aortic Aneurysm

“…Manipulating the metabolism of NAD + , the essential co-factor for SirT1 deacetylase activity, has proven very promising, as in some cases, it recapitulates the effects of resveratrol ( Baur, 2010 ). Both niacin and nicotinamide supplementation increases NAD + levels and NAD + -dependent SirT1 activity in aortas and prevents the development of AAA in mice ( Horimatsu et al, 2019 ). Similarly, nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, a methyltransferase crucial for the synthesis of the NAD + precursor nicotinamide mononucleotide ( Galli et al, 2013 ), has been shown to maintain aortic VSM integrity through NAD/SirT1 pathway ( Watson et al, 2017 ).…”

“…Therefore, the importance of developing pharmacological agents that activate an integrated response against oxidant stress in AA seems evident. Still, there is no definitive evidence from large scale clinical studies with anti-oxidant supplementation ( Egea et al, 2017 ), requiring a better understanding of how each compound would affect the sources of ROS in specific cell compartments, modulate NAD + levels ( Horimatsu et al, 2019 ), or affect ROS-induced reversible modifications, such as protein S-glutathionylation ( Shao et al, 2014 , 2017 ), for the suitable translation into clinical settings.…”

Aneurysms and dissections - What is new in the literature of 2019/2020 - a European Society of Vascular Medicine annual review

“…Targeting of the mechanistic target of rapamycin signaling pathway using rapamycin may be a favorable modulation for the clinical treatment of TAD [46]. Horimatsu et al report that niacin blunts aortic inflammation and matrix degradation, thereby suppressing AAA formation [47]. These effects are independent of the niacin receptor GPR109A and mimicked by nicotinamide, which does not induce flushing.…”