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Title: Comparison of the effects of dietary flavonoids and statins on lipopolysaccharide-induced vascular inflammation
Author: Alshalmani, Salmin Khalid
ISNI:       0000 0004 2709 1811
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2011
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Numerous epidemiological studies indicate that flavonoid intake as part of a balanced diet confers beneficial health effects in man, including improved cardiovascular function, reduced incidence of cancer and amelioration of symptoms associated with inflammatory disorders (Boots et al., 2008). A recent area of interest that may be fruitful is the study of anti-inflammatory effects of flavonoids in combination with statins. Porcine coronary artery (PCA) segments were incubated overnight at 37°C in modified Krebs-Henseleit solution with or without 1µg/ml lipopolysaccharides (LPS), with either (0.1–10µM) quercetin, or 10µM quercetin 3′-suphate and 10µM quercetin-3-glucuronide, or with (0.01-10µM) epicatechins, 10µM catecchin and10µM epigallocatechin gallate. (0.03-3µM) simvastatins and 10µM pravastatin are also used in this study. In addition, since many quercetin-rich foods also contain significant amounts of myricetin, this flavonoid has also been examined. After 16 to 18 hours, segments were prepared for isometric tension recording in Krebs-Henseleit solution. The segments were then exposed to cumulatively increasing concentrations of KCl and then U46619. Responses are shown as milliNewton or calculated as the concentration causing 50% of the maximum effect (-log EC50). For nitrite measurement, segments of the PCA were incubated in DMEM at 37°C for 24 hours, with or without 1μg/mL LPS. The nitrite content (nmol) of the bathing medium was determined by spectrophotometry using the Griess reaction, while inducible nitric oxide synthase was identified immunohistochemically. Differences between mean values were assessed by ANOVA (post-hoc Dunnett test). Prolonged exposure to LPS caused hyporesponsiveness of the PCA associated with increase in nitrite production by a mechanism that appears to involve the induction of nitric oxide synthase. Nitrite content of the incubation medium increased 3 to 10-fold following exposure to LPS and inducible nitric oxide synthase was detected in the adventitia. The results indicated that all of the tested flavonoids and statins are able to suppress LPS-induced changes in vascular responses, nitrite production and expression of inducible nitric oxide synthase. While 10µM myricetin was inactive. In conclusion I have demonstrated that quercetin, and its principal human metabolites and catechins oppose pro-inflammatory events in both endothelial cells and vascular smooth muscle cells. Possibly through a mechanism involving inhibition of NFkB. Since pre-treatment of the PCA with statins reduced LPS-induced changes in vasoconstrictor responses, suppressed the induction of nitric oxide synthase caused by LPS and the associated increase in nitrite production. It is unlikely that the effect of the statin involves direct inhibition of NOS. These findings are consistent with clinical studies suggesting that prior use of statins may afford protection against bacterial sepsis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QU Biochemistry