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Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide.
Cardiovasc Res. 2020 12 01; 116(14):2226-2238.CR

Abstract

AIMS

Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). 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.

CONCLUSION

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.

Authors+Show Affiliations

Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA. Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA, USA.Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA. Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA.Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA. Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA.Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Ludwigstraβe, Bad Nauheim, Germany.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

31710686

Citation

Horimatsu, Tetsuo, et al. "Niacin Protects Against Abdominal Aortic Aneurysm Formation Via GPR109A Independent Mechanisms: Role of NAD+/nicotinamide." Cardiovascular Research, vol. 116, no. 14, 2020, pp. 2226-2238.
Horimatsu T, Blomkalns AL, Ogbi M, et al. Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide. Cardiovasc Res. 2020;116(14):2226-2238.
Horimatsu, T., Blomkalns, A. L., Ogbi, M., Moses, M., Kim, D., Patel, S., Gilreath, N., Reid, L., Benson, T. W., Pye, J., Ahmadieh, S., Thompson, A., Robbins, N., Mann, A., Edgell, A., Benjamin, S., Stansfield, B. K., Huo, Y., Fulton, D. J., ... Kim, H. W. (2020). Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide. Cardiovascular Research, 116(14), 2226-2238. https://doi.org/10.1093/cvr/cvz303
Horimatsu T, et al. Niacin Protects Against Abdominal Aortic Aneurysm Formation Via GPR109A Independent Mechanisms: Role of NAD+/nicotinamide. Cardiovasc Res. 2020 12 1;116(14):2226-2238. PubMed PMID: 31710686.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide. AU - Horimatsu,Tetsuo, AU - Blomkalns,Andra L, AU - Ogbi,Mourad, AU - Moses,Mary, AU - Kim,David, AU - Patel,Sagar, AU - Gilreath,Nicole, AU - Reid,Lauren, AU - Benson,Tyler W, AU - Pye,Jonathan, AU - Ahmadieh,Samah, AU - Thompson,Allie, AU - Robbins,Nathan, AU - Mann,Adrien, AU - Edgell,Ashlee, AU - Benjamin,Stephanie, AU - Stansfield,Brian K, AU - Huo,Yuqing, AU - Fulton,David J, AU - Agarwal,Gautam, AU - Singh,Nagendra, AU - Offermanns,Stefan, AU - Weintraub,Neal L, AU - Kim,Ha Won, PY - 2019/05/22/received PY - 2019/10/23/revised PY - 2019/11/07/accepted PY - 2019/11/12/pubmed PY - 2021/8/24/medline PY - 2019/11/12/entrez KW - Abdominal aortic aneurysm KW - GPR109A KW - NAD+ KW - Nicotinamide KW - Nicotinic acid KW - Sirt1 SP - 2226 EP - 2238 JF - Cardiovascular research JO - Cardiovasc Res VL - 116 IS - 14 N2 - AIMS: Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). 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. CONCLUSION: 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. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/31710686/Niacin_protects_against_abdominal_aortic_aneurysm_formation_via_GPR109A_independent_mechanisms:_role_of_NAD+/nicotinamide_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvz303 DB - PRIME DP - Unbound Medicine ER -