Establishing basic biological mechanisms governing cardiovascular benefits

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The previous NSERC Discovery Grant allowed us to learn potential synergistic effects of dietary agents and anti-rejection drugs in a rat heart transplant model. Thus, in the proposed studies we want to utilize our experiences to further enhance our knowledge of basic mechanisms of the development and prevention of transplant coronary atherosclerosis usin a genetically modified mouse model. The following 3 aims will be included in these studies:Aim 1: Cardiovascular benefits including prevention of post heart transplant complications of dietary phytosterols and nitrites are medicated through alterations in immune system. We will perform heart transplant surgeries in mice. After a full recovery from surgery, the mice will be treated with experimental diets containing phytosterols alone or with nitrite or with probucol for 12 weeks. Both dietary phytosterols and nitrite are supposed to produce anti-inflammatory conditions and probucol will produce pro-inflammatory conditions. The state of inflammation will be studied by 4 distinct but interrelated methods including, estimation of plasma cytokine levels, response of spleen cells to a number of stimulants, investigation of inflammation-related gene expression in white blood cells, and finally identification of inflammatory cells and markers in atherosclerotic lesions using immunohistochemistry techniques. Aim 2: Cardiovascular benefits of dietary phytosterols and nitrite may be mediated through alterations in the coagulation system. We will feed these mice with the above mentioned diets for 6 months. A number of coagulatory factors and their gene expression will be studied and correlated with the extent and severity of atherosclerosis. Aim 3: Dietary phytosterols and nitrite preserve cardiac function and rhythm through an overall prevention of coronary atherogenesis. Our knowledge on the impact of coronary atherosclerosis on heart function is limited. Thus we will feed these mice with above-mentioned diets for 1 year to develop advanced heart disease. The mice will undergo echocardiography procedures to evaluate heart function every 8 weeks. At sacrifice the aorta will be examined using the novel and a sophisticated image analysis method.