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Plant-Derived Substances and Cardiovascular Diseases: Effects of Flavonoids, Terpenes and Sterols on Angiotensin-Converting Enzyme and Nitric Oxide
Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diet has for many years been known to play a key role in the development of chronic diseases. There are clear associations between consumption of vegetables, fruits and berries, and risk of cardiovascular diseases, the number one cause of death in the world. To maintain homeostasis of the vascular wall the balance between angiotensin II, nitric oxide and reactive oxygen species is of great importance in order to affect the development of cardiovascular diseases. Angiotensin II, a potent vasoconstrictor causing cell growth and nitric oxide, a signalling molecule influencing the vascular system as a vasodilatator, inhibiting cell proliferation and reactive oxygen species, are linked together in the renin-angiotensin aldosteron system. Angiotensin-converting enzyme will as a key enzyme in the reninangiotensin aldosteron system convert angiotensin I to form angiotensin II and nitric oxide is known to inhibit angiotensin-converting enzyme and act as a scavenger of reactive oxygen species. Plant-derived substances as flavonoids, tocopherols and carotenoids are shown to have beneficial effects on the cardiovascular system due to their antioxidative effects. The aims of this study were to investigate beverages, dietary products, herbal medicinal plants, α-tocopherol, β-carotene, sterols and lipidowering drugs on angiotensin-converting enzyme activity and nitric oxide concentrations. This was done to investigate if the sole mechanism of plant-derived substances is their antioxidative properties and to investigate if there is any connection between effect and biosynthesis/structure of plant substances. The tested infusions and extracts containing high amounts of flavonoids, the flavonoids and β-carotene significantly inhibited angiotensin-converting enzyme activity in vitro. The other substances tested did not affect, or in some cases significantly increased, angiotensin-converting enzyme activity. The infusions and extracts containing high amounts of flavonoids, the flavonoids andβ-carotene showed an increase on nitric oxide concentrations in vitro. Oral intake of a single dose of Rooibos tea significantly inhibited angiotensin-converting enzyme activity. A significant inhibition of angiotensin-converting enzyme activity was seen with the green tea for the angiotensin-converting enzyme genotypes II and ID. A significant inhibition of angiotensin-converting enzyme activity was also seen with the Rooibos tea for the angiotensin-converting enzyme genotype II.

Conclusion; flavonoids and β-carotene interact with the cardiovascular system in severalways, by reducing reactive oxygen species (as shown in several studies), increasing nitricoxide concentrations (as shown here and by others) and also by inhibiting angiotensinconvertingenzyme activity (as shown here). Infusions and extracts as tea containing highamounts of flavonoids function as angiotensin-converting enzyme inhibitors. Angiotensinconvertingenzyme contains two zink-dependent catalytic domains and angiotensinconvertingenzyme inhibitors are designed to bind to the Zn2+ at the active site. If theinhibitory mechanism of flavonoids on angiotensin-converting enzyme activity is due to theirability to bind to Zn2+ ions then it would be possible for the flavonoids to also inhibit otherzinc metallopeptidases, i.e. endothelin-converting enzyme, matrix metallopeptidases, neutralendopeptidase and maybe insulin-degrading enzyme, thereby exerting several additionalpositive effects on the cardiovascular system.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 127 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1097
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-45338Local ID: 81632ISBN: 978-91-7393-706-1 (print)OAI: oai:DiVA.org:liu-45338DiVA: diva2:266200
Public defence
2009-02-05, Linden, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Note
2009Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2009-10-16Bibliographically approved
List of papers
1. Tea flavanols inhibit angiotensin-converting enzyme activity and increase nitric oxide production in human endothelial cells
Open this publication in new window or tab >>Tea flavanols inhibit angiotensin-converting enzyme activity and increase nitric oxide production in human endothelial cells
2006 (English)In: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 58, no 8, 1139-1144 p.Article in journal (Refereed) Published
Abstract [en]

A diversity of pharmacological effects on the cardiovascular system have been reported for Camellia sinensis: antioxidative, antiproliferative and anti-angiogenic activity, and nitric oxide synthase activation. The purpose of this study was to investigate if the connection between tea and angiotensin-converting enzyme (ACE) and nitric oxide (NO) might be an explanation of the pharmacological effects of tea on the cardiovascular system. Cultured endothelial cells from human umbilical veins (HUVEC) were incubated with extracts of Japanese Sencha (green tea), Indian Assam Broken Orange Pekoe (black tea) and Rooibos tea, respectively. The main flavanols and purine alkaloids in green and black tea were examined for their effects on ACE and NO. After incubation with green tea, black tea and Rooibos tea for 10 min, a significant and dose-dependent inhibition of ACE activity in HUVEC was seen with the green tea and the black tea. No significant effect on ACE was seen with the Rooibos tea. After 10-min incubation with (-)-epicatechin, (-)- epigallocatechin, (-)-epicatechingallate and (-)-epigallocatechingallate, a dose-dependent inhibition of ACE activity in HUVEC was seen for all four tea catechins. After 24-h incubation, a significantly increased dose-dependent effect on NO production in HUVEC was seen for the green tea, the black tea and the Rooibos tea. After 24-h incubation with (-)-epicatechin, (-)-epigallocatechin, (-)-epicatechingallate and (-)-epigallocatechingallate, a dose-dependent increased NO production in HUVEC was seen. In conclusion, tea extracts from C. sinensis may have the potential to prevent and protect against cardiovascular disease. © 2006 The Authors.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-34910 (URN)10.1211/jpp.58.8.0016 (DOI)24032 (Local ID)24032 (Archive number)24032 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
2. Effect of Panax ginseng extract (G115) on angiotensin-converting enzyme (ACE) activity and nitric oxide (NO) production
Open this publication in new window or tab >>Effect of Panax ginseng extract (G115) on angiotensin-converting enzyme (ACE) activity and nitric oxide (NO) production
2006 (English)In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 105, no 3, 321-325 p.Article in journal (Refereed) Published
Abstract [en]

This study investigates the effects of the Panax ginseng (Araliaceae) extract G115 on angiotensin-converting enzyme (ACE) activity and nitric oxide (NO) in cultured human endothelial cells from umbilical veins (HUVEC) and bovine mesenteric arteries (BMA). In HUVEC, ACE activity was significantly reduced after 10 min incubation with aqueous extract of ginseng 5.0 and 10 mg/ml. This effect was additative with the inhibition of the traditional ACE inhibitor enalaprilat. No effect was seen on NO production from the cells. Angiotensin I-induced contraction of BMA was significantly attenuated by 0.1 and 0.5 mg/ml ginseng, while no endothelium-dependent or -independent relaxation was seen. In conclusion, extract of Panax ginseng (G115) inhibits ACE activity, but does not affect NO production in HUVEC and BMA. © 2005 Elsevier Ireland Ltd. All rights reserved.

Keyword
Panax ginseng; Angiotensin-converting enzyme; Nitric oxide; HUVEC
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-37111 (URN)10.1016/j.jep.2005.10.030 (DOI)33727 (Local ID)33727 (Archive number)33727 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
3. Effects of Ginkgo biloba extract EGb 761 and its terpenelactones on angiotensin converting enzyme activity and nitric oxide production in human endothelial cells
Open this publication in new window or tab >>Effects of Ginkgo biloba extract EGb 761 and its terpenelactones on angiotensin converting enzyme activity and nitric oxide production in human endothelial cells
2008 (English)In: Journal of traditional medicines, ISSN 1880-1447, Vol. 3, no 2, 42-51 p.Article in journal (Refereed) Published
Abstract [en]

The effects of Ginkga bi/aba (Ginkgoaceae), its terpene-Iactones (ginkgolide A, B, C and bilobalide), biflavonols (quercetin), biflavones (sciadopitysin) and proanthocyanidins (procyanidin) on angiotensin-converting enzyme (ACE) activity and nitric oxlde (NO) production in cultured human endothelial cells from umbilical veins (HUVEC) were investigated. A dose-dependent significant inhibition of the ACE activity was observed arter 10 min incubation with Ginkga bi/aba extract EGb  761 and quercetin. No significant effects due to terpene-Iactones or sciadopitysin were seen. Incubation with Ginkga bi/aba extract, quercetin, sciadopitysin and procyanidin for 24 hr significantly Increased NO production. No significant effects were seen with ginkgollde A, B and C, while bilobalide induced a dose-dependent decrease in NO production. In conclusion, this study shows that Ginkga bi/aba extract Inhibits ACE activlty and increases NO production from HUVEC. A flavonol (quercetin and/or homologs) is the main component responsible for the inhibitory effect ofACE activity. Quercetin and a proanthocyandin (procyanidin) are responsible for the increases seen in NO production. These results may explain the positive effects of Ginkga bi/aba on the cardiovascular system and on cognitive function.

Keyword
Angiotensin-converting enzyme; flavonoids; Ginkgo biloba; nitric oxide; terpene-lactones
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-44475 (URN)76784 (Local ID)76784 (Archive number)76784 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2011-01-11Bibliographically approved
4. Effect of Vaccinium myrtillus and Its Polyphenols on Angiotensin-Converting Enzyme Activity in Human Endothelial Cells
Open this publication in new window or tab >>Effect of Vaccinium myrtillus and Its Polyphenols on Angiotensin-Converting Enzyme Activity in Human Endothelial Cells
2009 (English)In: Journal of Agricultural and Food Chemistry, ISSN 0021-8561, Vol. 57, no 11, 4626-4629 p.Article in journal (Refereed) Published
Abstract [en]

This study investigates if the connection between Vaccinium myrtillus and angiotensin-converting enzyme (ACE) might be an explanation of the pharmacological effects on circulation. Cultured endothelial cells from human umbilical veins were incubated with bilberry 25E extract. The main anthocyanidins combined in myrtillin chloride and separately in cyanidin, delphinidin, and malvidin, respectively, were examined concerning their effects on ACE. After 10 min of incubation with bilberry 25E, a significant, dose-dependent inhibition of ACE activity was seen, and after incubation with myrtillin chloride a significant inhibition was seen. No effect was seen with the anthocyanidins. The effect seems to be dependent on this specific mixture of anthocyanins in the bilberry. V. myrtillus may thus have the potential to prevent and protect against cardiovascular diseases.

Keyword
Angiotensin-converting enzyme; Vaccinium myrtillus; anthocyanidins
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18654 (URN)10.1021/jf900128s (DOI)
Note
On the day of the defence date the status of this article was Submitted.Available from: 2009-06-03 Created: 2009-06-03 Last updated: 2009-10-16Bibliographically approved
5. Effects of green tea, black tea and rooibos on angiotensin-converting enzyme activity in healthy volunteers
Open this publication in new window or tab >>Effects of green tea, black tea and rooibos on angiotensin-converting enzyme activity in healthy volunteers
2009 (English)In: in Planta Medica(ISSN 0032-0943), 2009, Vol. 75, no 9, 1030-1030 p.Conference paper, Published paper (Refereed)
Abstract [en]

Tea has been reported to reduce cardiovascular mortality, but the mechanisms behind are largely unknown. The aim of this project was to investigate the effect of green tea (Japanese Sencha), black tea (Indian Assam B.O.P.) and Rooibos on angiotensin-converting enzyme and nitric oxide. Seventeen healthy volunteers received a single oral dose of either 400 ml green tea, black tea or Rooibos tea in a randomized three-phase cross over study. ACE activity and NO concentration were measured (at 0, 30, 60 and 180 minutes) in all phases. ACE activity was analysed with a commercial radioenzymatic assay. Nitrite was analysed as a marker of NO concentration. In addition ACE genotype was determined using a PCR method. Oral intake of a single dose of Rooibos significantly inhibited ACE activity, p<0.01 after 30 min and p<0.05 after 60 min. A significant inhibition of ACE activity was seen with green tea for the ACE genotype II (p<0.05), 30 minutes after intake of the tea and for the ACE genotype ID (p<0.05), 60 minutes after intake. A significant inhibition of ACE activity was also seen with Rooibos for the ACE genotype II (p<0.05), 60 minutes after intake. No significant effect on NO concentration was seen.

Keyword
Tea, angiotensin-converting enzyme, nitric oxide
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20327 (URN)
Note
On the day of the defence date the status of this article was Submitted.Available from: 2009-09-04 Created: 2009-09-04 Last updated: 2011-03-31Bibliographically approved

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