Nicotine promotes vascular calcification via intracellular Ca2+-mediated, Nox5-induced oxidative stress, and extracellular vesicle release in vascular smooth muscle cells.
Atherosclerosis
/ metabolism
Calcium
/ metabolism
Cardiovascular Diseases
/ metabolism
Cells, Cultured
Extracellular Vesicles
/ metabolism
Humans
Muscle, Smooth, Vascular
/ metabolism
Myocytes, Smooth Muscle
/ metabolism
NADPH Oxidase 5
/ metabolism
Nicotine
/ adverse effects
Oxidative Stress
Vascular Calcification
/ chemically induced
X-Ray Microtomography
Nicotine Vascular calcification Vascular smooth muscle cell phenotypic switching Nox5 Vitamin K2
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
20 07 2022
20 07 2022
Historique:
received:
17
06
2020
accepted:
15
07
2021
pubmed:
18
7
2021
medline:
26
7
2022
entrez:
17
7
2021
Statut:
ppublish
Résumé
Smokers are at increased risk of cardiovascular events. However, the exact mechanisms through which smoking influences cardiovascular disease resulting in accelerated atherosclerosis and vascular calcification are unknown. The aim of this study was to investigate effects of nicotine on initiation of vascular smooth muscle cell (VSMC) calcification and to elucidate underlying mechanisms. We assessed vascular calcification of 62 carotid lesions of both smoking and non-smoking patients using ex vivo micro-computed tomography (µCT) scanning. Calcification was present more often in carotid plaques of smokers (n = 22 of 30, 73.3%) compared to non-smokers (n = 11 of 32, 34.3%; P < 0.001), confirming higher atherosclerotic burden. The difference was particularly profound for microcalcifications, which was 17-fold higher in smokers compared to non-smokers. In vitro, nicotine-induced human primary VSMC calcification, and increased osteogenic gene expression (Runx2, Osx, BSP, and OPN) and extracellular vesicle (EV) secretion. The pro-calcifying effects of nicotine were mediated by Ca2+-dependent Nox5. SiRNA knock-down of Nox5 inhibited nicotine-induced EV release and calcification. Moreover, pre-treatment of hVSMCs with vitamin K2 ameliorated nicotine-induced intracellular oxidative stress, EV secretion, and calcification. Using nicotinic acetylcholine receptor (nAChR) blockers α-bungarotoxin and hexamethonium bromide, we found that the effects of nicotine on intracellular Ca2+ and oxidative stress were mediated by α7 and α3 nAChR. Finally, we showed that Nox5 expression was higher in carotid arteries of smokers and correlated with calcification levels in these vessels. In this study, we provide evidence that nicotine induces Nox5-mediated pro-calcific processes as novel mechanism of increased atherosclerotic calcification. We identified that activation of α7 and α3 nAChR by nicotine increases intracellular Ca2+ and initiates calcification of hVSMCs through increased Nox5 activity, leading to oxidative stress-mediated EV release. Identifying the role of Nox5-induced oxidative stress opens novel avenues for diagnosis and treatment of smoking-induced cardiovascular disease.
Identifiants
pubmed: 34273166
pii: 6323361
doi: 10.1093/cvr/cvab244
pmc: PMC9302892
doi:
Substances chimiques
Nicotine
6M3C89ZY6R
NADPH Oxidase 5
EC 1.6.3.-
NOX5 protein, human
EC 1.6.3.-
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2196-2210Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
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