Biomaterial Database

Nicotine promotes vascular calcification via intracellular Ca2+-mediated, Nox5-induced oxidative stress, and extracellular vesicle release in vascular smooth muscle cells. 2022

Ploingarm Petsophonsakul, and Mathias Burgmaier, and Brecht Willems, and Sylvia Heeneman, and Nadina Stadler, and Felix Gremse, and Sebastian Reith, and Kathrin Burgmaier, and Florian Kahles, and Nikolaus Marx, and Ehsan Natour, and Elham Bidar, and Michael Jacobs, and Barend Mees, and Chris Reutelingsperger, and Malgorzata Furmanik, and Leon Schurgers

Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

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.

UI	MeSH Term	Description	Entries
D009131	Muscle, Smooth, Vascular	The nonstriated involuntary muscle tissue of blood vessels.	Vascular Smooth Muscle,Muscle, Vascular Smooth,Muscles, Vascular Smooth,Smooth Muscle, Vascular,Smooth Muscles, Vascular,Vascular Smooth Muscles
D009538	Nicotine	Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke.	Nicotine Bitartrate,Nicotine Tartrate
D002118	Calcium	A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.	Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D002318	Cardiovascular Diseases	Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM.	Adverse Cardiac Event,Cardiac Events,Major Adverse Cardiac Events,Adverse Cardiac Events,Cardiac Event,Cardiac Event, Adverse,Cardiac Events, Adverse,Cardiovascular Disease,Disease, Cardiovascular,Event, Cardiac
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067128	Extracellular Vesicles	Membrane limited structures derived from cell membranes and cytoplasmic material, and released into EXTRACELLULAR SPACE. They circulate through the EXTRACELLULAR FLUID and through the peripheral blood in the MICROVASCULATURE where cells, much larger, cannot, thereby affecting a variety of intercellular communication processes.	Apoptotic Bodies,Exovesicles,Apoptotic Body,Bodies, Apoptotic,Body, Apoptotic,Exovesicle,Extracellular Vesicle,Vesicle, Extracellular,Vesicles, Extracellular
D000074664	NADPH Oxidase 5	An NADPH oxidase that contains four EF HANDS and is expressed primarily by SPERMATOCYTES and LYMPHOCYTES, as well as by endothelial cells. It functions as a calcium-dependent proton channel to generate SUPEROXIDES that regulate cell growth, APOPTOSIS; and PHYSIOLOGIC ANGIOGENESIS.	Nox5 Protein
D050197	Atherosclerosis	A thickening and loss of elasticity of the walls of ARTERIES that occurs with formation of ATHEROSCLEROTIC PLAQUES within the ARTERIAL INTIMA.	Atherogenesis,Atherogeneses,Atheroscleroses
D055114	X-Ray Microtomography	X-RAY COMPUTERIZED TOMOGRAPHY with resolution in the micrometer range.	MicroCT,Microcomputed Tomography,X-Ray Micro-CAT Scans,X-Ray Micro-CT,X-Ray Micro-CT Scans,X-Ray Micro-Computed Tomography,X-Ray Microcomputed Tomography,X-ray MicroCT,Xray Micro-CT,Xray MicroCT,Micro-CAT Scan, X-Ray,Micro-CAT Scans, X-Ray,Micro-CT Scan, X-Ray,Micro-CT Scans, X-Ray,Micro-CT, X-Ray,Micro-CT, Xray,Micro-CTs, X-Ray,Micro-CTs, Xray,Micro-Computed Tomography, X-Ray,MicroCT, X-ray,MicroCT, Xray,MicroCTs,MicroCTs, X-ray,MicroCTs, Xray,Microcomputed Tomography, X-Ray,Microtomography, X-Ray,Scan, X-Ray Micro-CAT,Scan, X-Ray Micro-CT,Scans, X-Ray Micro-CAT,Scans, X-Ray Micro-CT,Tomography, Microcomputed,Tomography, X-Ray Micro-Computed,Tomography, X-Ray Microcomputed,X Ray Micro CAT Scans,X Ray Micro CT,X Ray Micro CT Scans,X Ray Micro Computed Tomography,X Ray Microcomputed Tomography,X Ray Microtomography,X ray MicroCT,X-Ray Micro-CAT Scan,X-Ray Micro-CT Scan,X-Ray Micro-CTs,X-ray MicroCTs,Xray Micro CT,Xray Micro-CTs,Xray MicroCTs