Unravelling the mechanisms of vascular protection by omega-3 PUFAs to optimise and support their use as bioactives by the food industry

We know that diet plays a significant part in the risk of developing atherosclerosis and other blood vessel diseases. There is evidence that a fat found in fish oil and some plant oils, omega-3 polyunsaturated fatty acids (PUFA), reduces deaths from cardiovascular disease (CVD), and omega-3 PUFA are widely advertised and marketed as bioactives in food and health supplements. The food industry can only make accurate health claims about a product if they are based on good scientific understanding of its actions, but the reasons why omega-3 PUFA are beneficial are not defined. This project will address the urgent need for a better understanding of precisely how omega-3 PUFA protect arteries against the detrimental processes that damage vascular health. Many types of CVD begin when the layer of cells lining the arteries (endothelial cells; ECs) start to function abnormally. This causes white blood cells (monocytes) to enter the artery wall and turn into macrophages, which take up huge quantities of fat and eventually form fatty deposits in the artery wall. Thus, ECs and monocytes play crucial roles in determining the overall health of blood vessels and in CVD development. Fats from foods we consume are carried in the blood in microscopic particles known as chylomicron remnants (CMR). We have shown that fats from food can dramatically alter the functions of ECs, monocytes and macrophages during their transport in CMR and that this increases their ability to release factors which cause inflammation of the vessel wall, and their fat uptake, thus promoting the initiation of vascular damage. The overall aim of this project is to investigate the new idea that omega-3 PUFA protect against vascular dysfunction by modifying the interactions of CMR with these cell types, focusing particularly on ECs and monocytes since their impaired behaviour and interaction occurs earliest in the disease process. We hypothesise that omega-3 PUFA carried in CMR: reduce detrimental events inside the cells which promote the expression and release of molecules that cause inflammation and endothelial dysfunction; and activate protective intracellular events to increase the expression and release of molecules that limit these processes. To test these hypotheses we will use omega-3 PUFA from fish and vegetarian sources and human ECs and monocytes. We have established a method for making artificial CMRs that mimic exactly the effects of those that circulate in the blood stream. This enables us to incorporate omega-3 PUFA into the particles at different concentrations and to examine their specific effects on cultured human cells in comparison to other fats. To link these studies in our model systems with what happens in humans, we will also use CMR obtained from the blood of healthy volunteers given meals containing omega-3 PUFA or other fats. Alongside these studies we will use new techniques that allow us to examine in precise detail an enormous number of genes so that we can discover exactly which genes are altered by omega-3 PUFA, and how these differ from those changed by damaging fats. Current advice from the Scientific Advisory Committee on Nutrition to the general public is to increase the consumption of omega-3 PUFA, and as a result there is now considerable and growing interest from the food industry, and they are already being incorporated into common foodstuffs (eg. infant foods and margarines), and are promoted as health food supplements in capsule form. It is therefore essential for health professionals and the food industry, that the reasons why omega-3 PUFA help to preserve vascular health are properly understood. Our studies will provide comprehensive scientific information about how omega-3 PUFA protect against impaired vascular health when they are carried in CMR. Our mechanistic study will provide further support for, and underpin the endeavours of the food industry to develop healthy foods and accurately promote their health benefits.

Diet is an important factor in the risk of cardiovascular disease (CVD), and this has led to enormous interest in bioactives, food components which provide medical or health benefits, and how they may be exploited to produce healthier foods. This multi- and interdisciplinary collaborative project will investigate the mechanistic basis of the beneficial actions of omega-3 polyunsaturated fatty acids (PUFA), widely marketed as bioactives, on vascular health. CVD is characterised by inflammatory processes which begin with dysfunction of the vascular endothelium and increased migration of monocytes into the intima followed by the formation of macrophage foam cells. We have already shown that chylomicron remnants (CMR), the lipoprotein carriers of dietary lipids in the blood, directly influence endothelial cell (EC), monocyte and macrophage functions and that these effects are influenced by the type of fatty acids carried. This project will test the emerging hypothesis that in the postprandial phase omega-3 PUFA carried in CMR modulate the molecular events that promote vascular wall dysfunction by reducing the detrimental effects of the particles on ECs, monocyes and EC:monocyte interaction. This may occur by: suppressing pro-inflammatory/-oxidant signalling events regulating inflammatory gene expression; altering the balance of mediator release; and activating cytoprotective pathways. These studies will be complemented by parallel investigations of the cellular effects of particles isolated from fed humans, and of the effects of omega-3 PUFA-enriched CMRs on the molecular phenotype of vascular cells using bioinformatics. This project will provide highly novel insight into the molecular control of vascular cell function by omega-3 PUFA carried in CMRs in the postprandial phase. Understanding how dietary intake of omega-3 PUFA affects vascular health will allow the food industry to accurately promote their health benefits and underpin endeavours to develop healthy foods.

This project will benefit the food industry, health-conscious public and national/ international policy makers. Omega-3 PUFA (3PUFA) are widely accepted food supplements, but in the absence of understanding the cellular/molecular basis of their action, it is impossible to ensure their effective or optimal use. Indeed, evidence suggests that high doses of omega-3 PUFA can have unwanted effects such as increased risk of bleeding. It is also unclear whether vegetarian- or fish-derived 3PUFA act similarly; this impacts on dietary choices but could also inform management of commercial fish stocks since a sustainable fish supply is not guaranteed. The studies will help policy makers to improve and fully define nutritional advice given to the public by providing a scientific basis for the use of 3PUFA for health benefit. Since fish consumption and sustainability are key environmental issues the additional identification of the vascular actions of vegetarian sources of these fatty acids is particularly timely and will also be of direct benefit to those individuals who do not consume fish. Each area has social/economic impact: vascular actions of 3PUFA postprandially; equivalency of fish vs algal-derived 3PUFA; whether over-supplementation is wasteful or actively harmful. Working with the DRINC consortium will provide a route to address economic impact in development of products that are optimally 'healthy', produced economically and sustainably. The research will generate an essential mechanistic platform for the future development of new food/drink products containing fish- or plant-derived 3PUFA as bioactives and thus gives value to the industry in supporting product differentiation (eg. 3PUFA supplementation in baked/dairy products containing SFA). The studies will enable supplementation at a level appropriate for ensuring bioavailability and physiological activity (and health benefit), and provide a mechanism for testing the influence of processing and storage on bioavailability. The work will therefore impact on consumers, manufacturers and retailers. The incidence of cardiovascular disease in the UK is increasing and the aging population is a contributory factor. The new information gained from this project will benefit the population by promoting healthy aging and improved quality of life, leading to less economic drain on the health service through improved vascular health in later life. Atherosclerosis is a disease which develops over many years and overweight children as young as ten show clear evidence of the presence of disorders (eg diabetes) that facilitate the atherosclerotic lesion development that contributes to cardiovascular disease. Thus, the project will also provide support for advice on 3PUFA supplementation in children. People at increased risk of disease development through genetic predisposition will also benefit from the outcomes of the project in that advice could be targeted more appropriately. The academic research team is engaged with the food industry through collaboration and participation in the DRINC consortium, which provides a forum for dissemination of research results, ensuring they are taken into consideration in marketing of current foods and/or supplements, and particularly, in development of novel products. A website for this project will be established and will be directly linked to the RVC website. The data will also be made available to the wider scientific and medical community, industry and policy makers through talks/presentations and posters delivered at local, national and international conferences and by publication in international peer-reviewed journals covering vascular cell biology, nutrigenomics, nutrition, lipid signalling etc. The RVC employs Mistral PR to provide a full press office service. The importance of CVD and public interest in diet and health means that articles for popular science, lifestyle and food magazines are a further opportunity for dissemination.