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Effect of Nicotine and Nicotine Metabolites on Angiotensin-Converting Enzyme in Human Endothelial Cells
Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
2008 (English)In: Endothelium, ISSN 1062-3329, E-ISSN 1029-2373, Vol. 15, no 5-6, 239-245 p.Article in journal (Refereed) Published
Abstract [en]

Nicotine has been shown to induce endothelial dysfunction, which is an early marker of atherosclerosis. Nicotine undergoes extensive metabolism in the liver, forming a number of major and minor metabolites. There are very limited data on the effect of nicotine metabolites on the cardiovascular system. This study investigates the effects of nicotine and the nicotine metabolites, cotinine, cotinine-N-oxide, nicotine-1-N-oxide, norcotinine, trans-3-hydroxycotinine, on angiotensin-converting enzyme (ACE) in human endothelial cells. Cultured endothelial cells obtained from human umbilical cord vein (HUVECs) were stimulated with nicotine or nicotine metabolites in concentrations similar to those observed in plasma during smoking. ACE activity and expression were analyzed using commercial kits. The results showed that nicotine and nicotine metabolites can increase both activity and expression of ACE. However, a marked individual variation in the response to the drugs was observed. This variation was not associated with the ACE insertion/deletion polymorphism. Tobacco contains numerous chemical compounds, and the underlying cause for development of atherosclerosis in smokers is probably multifactorial. The results from this study could explain one cellular mechanism by which smoking exerts negative effect on the vascular system.

Place, publisher, year, edition, pages
2008. Vol. 15, no 5-6, 239-245 p.
Keyword [en]
Angiotensin-Converting Enzyme, Atherosclerosis, Endothelial Cells, Nicotine, Nicotine Metabolites, Tobacco
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-16216DOI: 10.1080/10623320802487627OAI: oai:DiVA.org:liu-16216DiVA: diva2:133459
Note
This is an electronic version of an article published in:Liza Ljungberg and Karin Persson, Effect of Nicotine and Nicotine Metabolites on Angiotensin-Converting Enzyme in Human Endothelial Cells, 2008, Endothelium, (15), 5-6, 239-245.Endothelium is available online at informaworldTM: http://dx.doi.org/10.1080/10623320802487627Copyright: Taylor & Francishttp://www.tandf.co.uk/journals/default.aspAvailable from: 2009-04-08 Created: 2009-01-09 Last updated: 2011-04-04Bibliographically approved
In thesis
1. Angiotensin-Converting Enzyme: Effects of Smoking and Other Risk Factors for Cardiovascular Diseases
Open this publication in new window or tab >>Angiotensin-Converting Enzyme: Effects of Smoking and Other Risk Factors for Cardiovascular Diseases
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Cardiovascular diseases (CVDs) are the most common cause of death in Western countries. Smoking, hypertension, diabetes mellitus and hypercholesterolemia are considered as major risk factors. However, the underlying mechanisms by which these factors cause CVDs are not entirely clear. Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin-aldosterone system, converting angiotensin I to the vasoactive peptide angiotensin II. Besides being an important factor for normal regulation of blood pressure, ACE appears to be involved in the pathogenesis of atherosclerosis. Previous studies have shown an upregulation of ACE in atherosclerotic plaques. There is genetic polymorphism in the ACE gene (ACE I/D polymorphism) which is strongly connected to the levels of ACE in plasma, but has also been associated with higher risk for cardiovascular diseases. The aim of this thesis was to investigate ACE in vitro and in vivo, in relation to cardiovascular risk factors and CVDs. The results showed that nicotine and nicotine metabolites increase ACE activity in human endothelial cells in vitro. Smoking was associated with increased plasma ACE levels. This effect might be mediated by nicotine and nicotine metabolites. These results could explain one cellular mechanism by which smoking exerts negative effect on the vascular system. Extract of oral snuff inhibited ACE in human endothelial cells and in serum, whereas extract of cigarette smoke had no effect on endothelial ACE. If these results have any physiological relevance remains to be investigated. Cardiovascular risk factors and CVDs were associated with increased levels of ACE in plasma. No association between ACE D/D genotype and CVDs was found. Based on these results we suggest that an increased level of ACE, rather than ACE genotype, is associated with increased risk for CVDs.

Abstract [sv]

Hjärtkärlsjukdomar är den vanligaste dödsorsaken i industriländer. Åderförkalkning är den bakomliggande process som orsakar hjärtkärlsjukdomar. En mängd olika riskfaktorer har identifierats (rökning, högt blodtryck, diabetes etc.) men man har inte helt lyckats kartlägga mekanismerna för hur dessa riskfaktorer leder till förkalkning av kärlen. Renin-angiotensin-aldosteron-systemet är ett av de viktigaste systemen i kroppen vad gäller reglering av blodtryck och vätske- och saltbalans. Angiotensin-converting enzyme (ACE) är ett nyckelenzym i reninangiotensin-aldosteron systemet och omvandlar angiotensin I till den aktiva peptiden angiotensin II. ACE är en central parameter för normal reglering av blodtryck, men man tror även att det är en viktig faktor för uppkomst av åderförkalkning. Tidigare studier har visat att individer med åderförkalkning har en ökad mängd ACE i det förkalkade området. Det finns en genetisk variation i genen för ACE som är starkt kopplad till mängd ACE i blodet. Ett antal studier har visat ett samband mellan denna genvariation och risken att drabbas av hjärtkärlsjukdomar, medan andra studier inte funnit detta samband. Syftet med denna avhandling var att undersöka ACE i relation till risk faktorer för hjärtkärlsjukdomar och förekomst av hjärtkärlsjukdomar. Resultaten visar att nikotin och levernedbrytningsprodukter av nikotin (nikotinmetaboliter) ökar aktiviteten av ACE i mänskliga endotelceller, den celltyp som täcker insidan av alla blodkärl. Dessutom visades att rökning resulterar i en ökad mängd ACE i blodet. Det är tänkbart att denna effekt orsakas av nikotin och nikotinmetaboliter och skulle kunna vara en mekanism för hur rökning ger upphov till hjärtkärlsjukdomar. Snus däremot minskade aktiviteten av ACE, medan cigarrettrök inte hade någon effekt. Dessutom visades att både riskfaktorer för hjärtkärlsjukdomar och förekomst av hjärtkärlsjukdomar resulterar i en ökad mängd ACE i blodet och vi föreslår att mängden ACE är en viktigare faktor än ACE-genvariant, vad gäller risken för att drabbas av hjärtkärlsjukdom.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 67 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 92
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16704 (URN)978-91-7393-712-2 (ISBN)
Presentation
2009-03-09, Linden, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Supervisors
Available from: 2009-02-12 Created: 2009-02-12 Last updated: 2013-07-04Bibliographically approved
2. Angiotensin-converting enzyme in cardiovascular function and dysfunction
Open this publication in new window or tab >>Angiotensin-converting enzyme in cardiovascular function and dysfunction
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system, converting angiotensin I to the vasoactive peptide angiotensin II, and degrading bradykinin. Angiotensin II is a multifunctional peptide, acting on a number of different tissues. A common genetic variation in the gene encoding ACE; ACE I/D polymorphism influences the level of ACE in the circulation, and has been linked to increased risk for cardiovascular disease. This thesis aimed to explore the connection between ACE and cardiovascular function and dysfunction.

The impact of nicotine and nicotine metabolites on ACE in cultured human endothelial cells was studied. Nicotine as well as nicotine metabolites induced increased ACE activity in cultured human endothelial cells. In elderly men a higher ACE level was seen in smokers compared to non-smokers. Furthermore, diabetes was associated with higher circulating ACE. Increased ACE level may represent a cellular mechanism which contributes to vascular damage.

Elderly men carrying the ACE D allele had higher abdominal aortic stiffness compared to men carrying the I/I genotype. Our data suggest that the mechanism by which the ACE D allele modulates aortic wall mechanics is independent of circulating ACE levels. Previous studies have indicated a link between the D allele and abdominal aortic aneurysm. Increased aortic stiffness suggests impaired vessel wall integrity, which combined with local hemodynamic and/or inflammatory factors may have a role in aneurysm formation.

Subjects with left ventricular dysfunction had higher levels of circulating ACE compared to those with normal left ventricular function, while there was no association between ACE and central hemodynamics. ACE might play a role in the pathogenesis of left ventricular dysfunction and our findings suggest a direct effect on the heart rather than affecting central blood pressure.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 73 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1224
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67215 (URN)978-91-7393-243-1 (ISBN)
Public defence
2011-04-15, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2011-04-04 Created: 2011-04-04 Last updated: 2017-03-27Bibliographically approved

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