1a. Objectives (from AD-416)
1. Identify bioactive food components and food patterns that inhibit atherosclerosis and angiogenesis using cell culture and animal models under the following sub-objectives: a) Determine bioavailability of avenanthramides from oats and characterize their potency and molecular mechanism of inhibition of vascular smooth muscle cell proliferation using cell culture systems and the femoral artery injury mouse model. b) Elucidate the molecular mechanism of catechins and curcumin and other dietary bioactive compounds on the inhibition of angiogenesis associated with adipose tissue growth and obesity. c) Determine the comparative bioavailability and biopotency of tocopherols versus tocopheryl phosphate on the inhibition of femoral artery injury model of vascular atherosclerosis and restenosis. 2. Determine the anti-inflammatory and anti-proliferative effects of avenanthramides of oats and derivatives on several colonic cancer cells lines and mouse models of inflammatory bowel disease and colon cancer.
1b. Approach (from AD-416)
The main objective of this project plan is to determine bioavailability, potency and mechanism of action of several bioactive food components, including avenanthramides(Avns) of oats, curcumin of turmeric, catechins of green tea and isomers of tocopherol in the prevention of atherosclerosis and angiogenesis as they relate to CVD, obesity and cancer. Specifically, we will determine bioavailability of Avns from oats and characterize their potency and mechanism of inhibition of vascular smooth muscle cell proliferation using cell culture and the femoral artery injury mouse model. Further, we will investigate the anti-inflammatory and antiproliferative effects of Avns of oats and derivatives on several cancer cells lines and mouse models of inflammatory bowel disease and colon cancer. We will also elucidate the molecular mechanism of catechins and curcumin and other dietary bioactive compounds on the inhibition of angiogenesis associated with adiposity and obesity. We also plan to investigate the comparative biopotency of' alpha-tocopherol (alpha-T) versus alpha-tocopheryl phosphate (alpha-TP) on the inhibition inflammatory cytokines and monocyte adhesion in cell culture systems and on comparative bioavailability and efficacy of alpha-T vs. alpha-TP on femoral artery injury model of atherosclerosis.
3. Progress Report
1. In an earlier study we found that supplementing high fat diet of mice with 500 mg curcumin, a bioactive component of turmeric spice, reduced body weight gain and total body fat. From cell culture studies we found that curcumin reduces fat accumulation in fat cells, macrophages,and immune system cells. We have discovered this effect of curcumin is partly related to its suppression of a molecule called fatty acid binding protein (FABP-4) or aP2. Thus, we studied 3 dose levels of curcumin to prevent atherosclerosis (disease of arteries) in LDL receptor knockout (LDLr-/-) mice, an animal model for human atherosclerosis. Curcumin dose-dependently prevented body weight gain and total body fat without affecting food intake or fat absorption from the gut. Curcumin also reduced atherosclerosis in these mice. When macrophage cells were exposed to curcumin, they time dependently increased activation of a cellular transcription factor called FOXO3a, which is centrally involved in regulating several stress resistance genes that modulate aging, cardiovascular disease, and cancer. 2. We discovered that alphaTocopherol phosphate (aTP), a natural derivative of vitamin E, is a lipid mediator and modulates molecular signals in cells to maintain cellular homeostasis and survival. In addition, gene array analysis revealed that aTP in human monocytic immune cells may accelerate lipid metabolism by decreasing fat formation and increasing fat burning. 3. We found that the level of acute phase protein (CRP), an inflammatory marker, in liver of old mice and in rats fed high fat diet or alcohol+lycopene was high. Supplementing mice with vitamin E mixture (tocopherol/tocotrienol) reduces it. Mice fed Western style, high fat diet also had high levels of CRP. Long-term folate (B vitamin) supplementation in mice increased the CRP levels in liver and reduced the arterial relaxation. Thus, Western style diet and too much folate supplementation increases inflammation and disturbs vascular function. 4. We found that mice fed a natural form of vitamin E genetically respond differently from those fed the synthetic form of vitamin E. This was well distinguishable when immune cells were tested. For publications related to project see parent project # 1950-51000-067-00D.
1. Anti-obesity and anti-atherosclerotic effect of curcumin in turmeric. Curcumin is known for its anti-inflammatory and anti-cancer activity. ARS-funded researchers from Tufts University, Boston MA have established in an animal model that curcumin, a bioactive component in turmeric spice, can prevent body weight gain. This is done through increasing burning of body fat and by suppressing growth of new blood vessels in fat tissue. In addition, we found that curcumin at low doses, not high doses, is effective at reducing vascular injury in a susceptible mouse model that has been fed Western style high fat diet. The anti-obesity effect of curcumin is a significant finding in relation to dietary factors that can help reduce the epidemic of obesity.