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Angiotensin-converting enzyme in cardiovascular function and dysfunction
Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-67215ISBN: 978-91-7393-243-1OAI: oai:DiVA.org:liu-67215DiVA: diva2:408337
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: 2012-01-09Bibliographically approved
List of papers
1. Effect of Nicotine and Nicotine Metabolites on Angiotensin-Converting Enzyme in Human Endothelial Cells
Open this publication in new window or tab >>Effect of Nicotine and Nicotine Metabolites on Angiotensin-Converting Enzyme in Human Endothelial Cells
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.

Keyword
Angiotensin-Converting Enzyme, Atherosclerosis, Endothelial Cells, Nicotine, Nicotine Metabolites, Tobacco
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16216 (URN)10.1080/10623320802487627 (DOI)
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
2. The association between circulating angiotensin-converting enzyme and cardiovascular risk in the elderly: A cross-sectional study.
Open this publication in new window or tab >>The association between circulating angiotensin-converting enzyme and cardiovascular risk in the elderly: A cross-sectional study.
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2011 (English)In: jraas. Journal of the renin-angiotensin-aldosterone system, ISSN 1470-3203, E-ISSN 1752-8976, Vol. 12, no 3, 281-289 p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: A polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) has been associated with increased risk for cardiovascular disease (CVD). This polymorphism affects the level of circulating ACE, but there is great individual variation, even between those with the same genotype. Few previous studies have investigated the link between circulating ACE and cardiovascular risk. The aim of this study was to investigate this association, and to examine the relationship between ACE level, ACE genotype and CVD.

MATERIALS AND METHODS: The study population consisted of 322 men and 350 women aged 69-87. Plasma ACE level was determined using enzyme-linked immunosorbent assay (ELISA), and ACE genotype was analysed using PCR followed by gel electrophoresis.

RESULTS: In men, ACE levels increased with increasing number of cardiovascular risk factors (p = 0.003). There was a significant association in men between increased ACE level and both diabetes (p = 0.007) and smoking (p = 0.037).

CONCLUSIONS: This study shows that cardiovascular risk factors (such as smoking and diabetes) are associated with higher levels of circulating ACE in men. High ACE levels may represent one of the cellular mechanisms involved in producing the vascular damage associated with cardiovascular risk factors.

Place, publisher, year, edition, pages
SAGE, 2011
Keyword
Cardiovascular risk factors, dibetes, endothelium, genetics, smoking
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67208 (URN)10.1177/1470320310391326 (DOI)000294450600019 ()21273224 (PubMedID)
Note
Funding Agencies|Cardiovascular Inflammatory Research Center, Linkoping, Sweden||Swedish Research Council|
1216
|Elanora Demeroutis Foundation, Linkoping, Sweden|
LIO-28471
|Goljes Memorial Foundation, Sweden|
LA2009-0119
|Medical Research Council of South East Sweden|
FORSS-34931
|Available from: 2011-04-04 Created: 2011-04-04 Last updated: 2013-09-26Bibliographically approved
3. Impaired abdominal aortic wall integrity in elderly men carrying the angiotensin-converting enzyme D allele
Open this publication in new window or tab >>Impaired abdominal aortic wall integrity in elderly men carrying the angiotensin-converting enzyme D allele
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2011 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 42, no 3, 309-316 p.Article in journal (Refereed) Published
Abstract [en]

Objective: A genetic polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) has been associated with abdominal aortic aneurysm and a link between aortic aneurysm and aortic stiffness has been suggested. The aim of this study was to explore the links between ACE I/D polymorphism, circulating ACE, and abdominal aortic wall integrity as reflected by abdominal aortic wall stiffness.

Material: The study population consisted of 406 subjects (212 men and 194 women) aged 70-88 years.

Methods: The mechanical properties of the abdominal aorta were determined 3-4 cm proximal to the aortic bifurcation using a Wall Track System. ACE-genotype was determined by PCR followed by gel electrophoresis, and circulating ACE level was measured by ELISA.

Results: Men carrying the ACE D allele had lower distensibility coefficient than II carriers (ID/DD 8.09 vs II 10.38, P=0.017). Multiple regression analyses showed additional associations between the ACE D allele and increased stiffness β as well as reduced cross-sectional compliance.

Conclusion: This study showed that men carrying the ACE D allele have stiffer abdominal aortas compared to II carriers. Deranged abdominal aortic stiffness indicates impaired vessel wall integrity, which along with other local predisposing factors, may be of importance in aneurysmal disease.

Place, publisher, year, edition, pages
Elsevier, 2011
Keyword
Aorta; Arterial stiffness; Distensibility; Gene polymorphism; Mechanical properties
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67213 (URN)10.1016/j.ejvs.2011.04.010 (DOI)000295061800007 ()
Available from: 2011-04-04 Created: 2011-04-04 Last updated: 2013-09-26Bibliographically approved
4. Circulating angiotensin-converting enzyme levels are associated with left ventricular dysfunction, but not with central aortic blood pressure, aortic augmentation or pulse pressure amplification
Open this publication in new window or tab >>Circulating angiotensin-converting enzyme levels are associated with left ventricular dysfunction, but not with central aortic blood pressure, aortic augmentation or pulse pressure amplification
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2011 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Aim: This study aimed to explore the link between angiotensin-converting enzyme (ACE), and left ventricular (LV) function and central hemodynamics.

Methods and Results: The study population consisted of 672 subjects (322 men and 350 women) aged 69-87 years. LV function was evaluated semi-quantitatively by visual estimation using echocardiography. Central aortic blood pressure, aortic augmentation and pulse pressure amplification were determined in a sub-group of 422 subjects by the use of the SphygmoCor system. ACE genotype was determined by PCR and circulating ACE levels were analysed using enzyme-linked immunosorbent assay (ELISA).

LV dysfunction was associated with higher levels of circulating ACE compared to subjects with normal LV function (p=0.007). This association remained after adjustment for factors previously shown to affect circulating ACE (ACE-genotype, age, diabetes and smoking) (p=0.036). There was a significant association between ACE level and degree of LV dysfunction (p=0.019). However, there was no association of ACE genotype or circulating ACE with central aortic blood pressure, aortic augmentation or pulse pressure amplification.

Conclusion: Subjects with LV dysfunction have higher levels of circulating ACE compared to subjects with normal LV function. ACE might play a role in the pathogenesis of LV dysfunction and our data indicates a direct effect on the heart rather than affecting central blood pressure.

Keyword
ACE, Heart Failure, Polymorphism, Renin-Angiotensin System, Central hemodynamics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67214 (URN)
Available from: 2011-04-04 Created: 2011-04-04 Last updated: 2013-09-26Bibliographically approved

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