Investigating the impact of flavonoid metabolites on endothelial function and vascular inflammation

The consumption of dietary flavonoids has been associated with reduced cardiovascular disease risk, however, many in vitro studies have demonstrated effects using supraphysiological concentrations of flavonoids, overlooking the potential bioactivity of flavonoid metabolites and additive effects in combination. This thesis investigated metabolite activity relative to their unmetabolised precursors, their additive activities, and mechanisms of action, on vascular and inflammatory biomarkers of endothelial dysfunction. 20 flavonoids and metabolites were screened for their effects on endothelial nitric oxide synthase (eNOS), haem oxygenase-1 (HO-1/Hmox-1), and vascular cell adhesion molecule-1 (sVCAM-1) in endothelial and smooth muscle cells. Active treatments were further explored for effect of concentration, mRNA response, and mechanisms of action (e.g. Nrf2 and NFB). Additionally, up to 25 combinations of flavonoids and metabolites were explored, reflecting 3 unique serum profiles of cyanidin-3-glucoside (C3G) metabolites observed in vivo post-consumption. HO-1 was increased >20 % in response to quercetin and 2 phenolic acids, of which only quercetin increased Nrf2 activation (3 fold), suggesting metabolites act on alternative pathways to their precursors. 4 combinations of protocatechuic acid (PCA) and PCA-conjugates significantly increased Hmox-1 (8.7-15.7 %), signifying additive effects. sVCAM-1 secretion was inhibited in response to 4 phenolic metabolites (10.1-17.2 %) but not their precursor structures, suggesting that metabolites are more active than their precursors in inflammatory mechanisms of action. sVCAM-1 was also inhibited in response a C3G metabolite profile reflecting 24 h (27.84 %) post-bolos sampling, but not at 1 h, indicating that anti-inflammatory activities of flavonoid metabolites are modulated by metabolites of microbial action which appear many hours post-consumption. Data herein suggest multiple mechanisms are modulated by flavonoid metabolites which contributes to our understanding of how flavonoids influence physiological responses, and therefore the associations between diet and health.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of East Anglia

Year dc:date.issued

2016

Author dc:creator

• Warner, Emily F

Language dc:language

en