Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: Role of NAD1/nicotinamide

Tetsuo Horimatsu, Andra L. Blomkalns, Mourad Ogbi, Mary Moses, David Kim, Sagar Patel, Nicole Gilreath, Lauren Reid, Tyler W. Benson, Jonathan Pye, Samah Ahmadieh, Allie Thompson, Nathan Robbins, Adrien Mann, Ashlee Edgell, Stephanie Benjamin, Brian K. Stansfield, Yuqing Huo, David J. Fulton, Gautam AgarwalNagendra Singh, Stefan Offermanns, Neal L. Weintraub, Ha Won Kim

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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 Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or and results 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 (NADþ) levels and NADþ-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 NADþ precursor. Supplementation of NADþ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.

Original languageEnglish (US)
Pages (from-to)2226-2238
Number of pages13
JournalCardiovascular Research
Volume116
Issue number14
DOIs
StatePublished - Dec 1 2020

Keywords

  • Abdominal aortic aneurysm
  • GPR109A
  • NADþ
  • Nicotinamide
  • Nicotinic acid
  • Sirt1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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