Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide.
Angiotensin II
Animals
Aorta, Abdominal
/ drug effects
Aortic Aneurysm, Abdominal
/ chemically induced
Calcium Chloride
Cells, Cultured
Dilatation, Pathologic
Disease Models, Animal
Male
Mice, Inbred C57BL
Mice, Knockout
NAD
/ metabolism
Niacin
/ pharmacology
Niacinamide
/ pharmacology
Receptors, G-Protein-Coupled
/ genetics
Receptors, LDL
/ genetics
Signal Transduction
Sirtuin 1
/ metabolism
Abdominal aortic aneurysm
GPR109A
NAD+
Nicotinamide
Nicotinic acid
Sirt1
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
01 12 2020
01 12 2020
Historique:
received:
22
05
2019
revised:
23
10
2019
accepted:
07
11
2019
pubmed:
12
11
2019
medline:
24
8
2021
entrez:
12
11
2019
Statut:
ppublish
Résumé
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. 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. 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.
Identifiants
pubmed: 31710686
pii: 5618721
doi: 10.1093/cvr/cvz303
pmc: PMC7695356
doi:
Substances chimiques
Hcar2 protein, mouse
0
Receptors, G-Protein-Coupled
0
Receptors, LDL
0
NAD
0U46U6E8UK
Angiotensin II
11128-99-7
Niacinamide
25X51I8RD4
Niacin
2679MF687A
Sirt1 protein, mouse
EC 3.5.1.-
Sirtuin 1
EC 3.5.1.-
Calcium Chloride
M4I0D6VV5M
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2226-2238Subventions
Organisme : NEI NIH HHS
ID : R01 EY029318
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL126949
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142097
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.
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