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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.

Cardiovascular disease is a broad term describing disease of the heart and/or blood vessels. The main blood vessel supplying the body with oxygenated blood is the aorta. The aorta may become affected in diseases such as atherosclerosis and aneurysm. Researchers investigating these diseases would benefit from direct observation of the aorta to characterize disease progression as well as to evaluate efficacy of potential therapeutics. The goal of this protocol is to describe proper isolation and excision of the aorta to aid investigators researching cardiovascular disease. Isolation and excision of the aorta allows investigators to look at gross morphometric changes as wells as allowing them to preserve and stain the tissue to look at histologic changes if desired. The aorta may be used for molecular studies to evaluate protein and gene expression to discover targets of interest and mechanisms of action. This technique is superior to imaging modalities as they have inherent limitations in technology and cost. Additionally, primary isolated cells from a freshly isolated and excised aorta can allowing researchers to perform further in situ and in vitro assays. The isolation and excision of the aorta has the limitation of having to sacrifice the animal however, in this case the benefits outweigh the harm as it is the most versatile technique in the study of aortic disease. Video LinkThe video component of this article can be found at

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Introduction. Abdominal aortic aneurysms (AAAs) are common among the aging population, yet there is no effective pharmacotherapy. Neutrophils play a key role in the pathogenesis of AAA, by triggering inflammation, oxidative stress, matrix degradation and smooth muscle cell (SMC) death. Niacin, a vitamin with beneficial cardiovascular effects, was shown previously to reduce vascular neutrophil infiltration, MPO accumulation, and HOCl-induced endothelial dysfunction in a rabbit perivascular injury model. Hypothesis We hypothesized that niacin would have beneficial effects to prevent AAA in a mouse model. Methods LDL null mice were infused with angiotensin II (1000 ng/kg/min) for 14 days to induce AAA with (n=27) or without (n=18) 0.3% supplemental niacin in the drinking water. One group (n=6) received the DP1 receptor antagonist, laropiprant, in addition to niacin. We also investigated the effects of niacin on MMP release in a human neutrophil cell line (HL-60) and on viability of a murine SMC line (MOVAS-1) challenged with 100μM H 2 O 2 . Results Niacin decreased the rate of AAA formation as compared to untreated control mice, 26% vs. 83%, respectively. In mice that survived the complete 14 day treatment period and did not die due to a ruptured AAA, the mean suprarenal aorta diameters were 1.20 mm (SEM 0.09) in niacin treated mice vs. 1.68 mm (SEM 0.12) in the control group, representing a niacin treatment effect of a 29% diameter decrease (p<0.5). Laropiprant did not have an effect on AAA formation, however did increase the blood pressure moderately. In HL-60 cells stimulated with TNF-α, niacin (10mM) decreased MMP 9 activity by 88% but had no effect on cell viability. In MOVAS-1 cells exposed to hydrogen peroxide, 10mM niacin had a protective effect, reducing cell death at 12 hours (50% dead cells with niacin + H 2 O 2 vs. 93% dead cells with hydrogen peroxide alone, p=0.02). Conclusions We conclude that niacin decreases the incidence of AAA and demonstrates pleiotropic effects on neutrophils and SMCs that may underlie its already known beneficial lipid modifying mechanisms. These novel findings suggest that niacin might be a safe, effective and inexpensive medical therapy for AAA.