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Dietary activators of antioxidant response element-linked gene expression for good vascular health

Reference	BB/G005699/1
Principal Investigator / Supervisor	Professor Paul Thornalley
Co-Investigators / Co-Supervisors	Dr Guy Barker, Professor Vicky Buchanan-Wollaston, Professor Sudhesh Kumar, Professor David Pink, Dr Naila Rabbani, Professor David Rand
Institution	University of Warwick
Department	Warwick Medical School
Funding type	Research
Value (£)	654,256
Status	Completed
Type	Research Grant
Start date	01/10/2008
End date	29/02/2012
Duration	41 months

Abstract

Epidemiological studies have shown that increased consumption of vegetables and fruit is associated with improved vascular health. The key to their benefit is probably their ability to induce and increase endogenous enzymatic defences against vascular cell damage and suppress dyslipidaemia. High expression of a battery of protective genes is achieved through activated by of transcription factor nrf2 binding to a functional promoter 'antioxidant response element' (ARE)'. At quiescence, nrf2 is held in the cytosol; on activation, it undergoes nuclear translocation, binding to AREs and increasing protective gene expression. Increased levels of ARE-linked gene products provide for enhanced protection of the vascular cell proteome and lipidome and suppression of lipogenesis. Non-nutrients in fruit and vegetables associated with nrf2-activating activity and improved vascular health are: oxidised omega-3 fatty acids, carotenoids, glucosinolate-derived isothiocyanates and indoles, polyphenols, and allyl sulphides. It is not clear currently which of these compounds or compound combinations is most effective in enhancing ARE-linked protective responses. The aim of this project is to employ human vascular endothelial and hepatocyte cell lines expressing a fluorescent nrf2 reporter in vitro to identify dietary bioactive compounds that provide potent and enduring activation of nrf2. Nrf2 activator contents of a variety of plants lines will be characterised. Bioactive compounds will be evaluated for ability to enhance vascular health by assessing increased nrf2 activation, ARE-linked gene expression, decreased proteome and lipidome damage and decreased lipogenesis. Mathematical models of the nrf2 anti-stress gene regulator system will be refined to predict dietary exposure-vascular health benefits. Findings will be translated clinically by study of healthy volunteers with dietary supplements of rapeseed oil, tomatoes, broccoli and Rocket salad - foodstuffs rich in bioactives.

Summary

Studies of human populations and their eating habits have shown that increased consumption of vegetables and fruit is associated with decreased risk of heart disease and stroke. This suggests these foodstuffs keep major blood vessels in a good state. Fruit and particularly Brassica vegetables (broccoli, cabbage, cauliflower and Brussel sprouts) are important components of a healthy diet because they have high levels of compounds linked to low risk of heart disease. The key to their benefit is probably their ability to induce and increase endogenous defences against blood vessel damage and counter the development of high cholesterol and lipids in the body. Good health of blood vessels is associated with a high production of proteins encoded by a battery of genes associated with maintenance of good blood vessel structural and function. The protective genes are regulated through interactions with at a section of their DNA called an 'antioxidant response element (ARE)'. Increased production of protective proteins is achieved by stimulating a protein called 'nrf2' that normally residues in the cell but outside of the cell nucleus to move into the nucleus. In the normal state, nrf2 is held predominantly outside the nucleus; on stimulation, it moves into the nucleus, bunds protective genes and makes them produce more of their encoded protein. Increased levels of ARE-linked gene proteins provide for increased protection against spontaneous damage in the blood vessels / by reactions with oxygen, reactive nitrogen species and sugars - preserving the structure and functions of proteins and lipids within the blood vessels. A further remarkable property of nrf2 is its ability to switch off certain ARE-linked genes / particularly those associated with the excessive production of cholesterol and lipids. Minor components in fruit and vegetables can stimulate nrf2 to do this. We think the most important components are: products derived from so-called 'omega-3 fatty acids' found in vegetables oils ('Canola'), carotenoids / compounds traditionally found in carrots but also in other vegetables, glucosinolates / compounds found in Brassica vegetables and also in increasingly popular 'Rocket' salad, polyphenols / compounds found in grape juice and also in onions, and alkyl disulphides / compounds found in onions and garlic. It is not clear currently which of these groups of compounds and members thereof are most effective in enhancing the ARE-linked protective responses in blood vessels. The aim of this project is to use two human cell lines / cells originating from human tissue but now grow continuously in culture, a cell typical of those found in blood vessels and one typical of liver cells (where cholesterol and lipids are made) / that have been genetically modified to produce nrf2 with a green fluorescence. We can them study nrf2 movement into the nucleus in responsive to compounds from fruit and vegetable under the microscope and make a time-lapsed video. Compounds from fruit and vegetables will be studied for their ability to produce strong and prolonged activation of nrf2 and associated cell protection from damage and accumulation of lipids. Compounds from many plant varieties will be studied to fine the plants best for enhancing cell health. Mathematical models of the nrf2 effects will be refined to predict health benefits from fruit and vegetable consumption. Finally, we will study the health of blood vessels in healthy human volunteers during periods when we supplement their diet successively with vegetable oil, tomato juice/paste, broccoli and Rocket salad. Successful completion of this project will reveal the varieties of common fruit and vegetables that are likely most beneficial in maintaining blood vessels in a good state and also which fruit and vegetables have the ability to decrease bad cholesterol and lipids and raise good cholesterol, and likely beneficial if include in our diets for current and future generations.

Committee	Closed Committee - Agri-food (AF)
Research Topics	Ageing, Diet and Health
Research Priority	X – Research Priority information not available
Research Initiative	Diet and Health Research Industry Club (DRINC) [2008-2014]
Funding Scheme	X – not Funded via a specific Funding Scheme

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