Petsophonsakul, Ploingarm ORCID: 0000-0002-0811-9992, Burgmaier, Mathias, Willems, Brecht, Heeneman, Sylvia, Stadler, Nadina, Gremse, Felix, Reith, Sebastian, Burgmaier, Kathrin, Kahles, Florian, Marx, Nikolaus, Natour, Ehsan, Bidar, Elham, Jacobs, Michael, Mees, Barend, Reutelingsperger, Chris, Furmanik, Malgorzata and Schurgers, Leon ORCID: 0000-0001-7867-6957 . Nicotine promotes vascular calcification via intracellular Ca2+-mediated, Nox5-induced oxidative stress, and extracellular vesicle release in vascular smooth muscle cells. Cardiovasc. Res.. OXFORD: OXFORD UNIV PRESS. ISSN 1755-3245

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Abstract

Aims 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. Methods and results We assessed vascular calcification of 62 carotid lesions of both smoking and non-smoking patients using ex vivo micro-computed tomography (mu CT) 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 alpha-bungarotoxin and hexamethonium bromide, we found that the effects of nicotine on intracellular Ca2+ and oxidative stress were mediated by alpha 7 and alpha 3 nAChR. Finally, we showed that Nox5 expression was higher in carotid arteries of smokers and correlated with calcification levels in these vessels. Conclusion 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 alpha 7 and alpha 3 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Petsophonsakul, PloingarmUNSPECIFIEDorcid.org/0000-0002-0811-9992UNSPECIFIED
Burgmaier, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willems, BrechtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heeneman, SylviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stadler, NadinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gremse, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reith, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burgmaier, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kahles, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marx, NikolausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Natour, EhsanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bidar, ElhamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jacobs, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mees, BarendUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reutelingsperger, ChrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Furmanik, MalgorzataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schurgers, LeonUNSPECIFIEDorcid.org/0000-0001-7867-6957UNSPECIFIED
URN: urn:nbn:de:hbz:38-594711
DOI: 10.1093/cvr/cvab244
Journal or Publication Title: Cardiovasc. Res.
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1755-3245
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CORONARY-ARTERY CALCIFICATION; NECROSIS-FACTOR-ALPHA; VITAMIN-K; CIGARETTE-SMOKING; FETUIN-A; SUBCLINICAL ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; CALCIUM-PHOSPHATE; AORTIC-ANEURYSMS; UP-REGULATIONMultiple languages
Cardiac & Cardiovascular SystemsMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59471

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