Project 1:  Mechanisms of Atherosclerosis Prevention by Flaxseed Oil

Project Leader: Lawrence Rudel, Ph.D.
Floyd (Ski) H. Chilton, III, Ph.D., Co-Investigator
John S. Parks, Ph.D., Co-Investigator
Iris Edwards, Ph.D. - Co-Investigator

Project 1 is designed to investigate the hypothesis that seed oil from flax (Linum usitatissium) provides effective protection against the development of atherosclerosis through its effects on plasma lipoprotein compositions and concentrations and on inflammatory responses of macrophages. Flaxseed oil as a food supplement is widely believed to have beneficial effects on coronary heart disease (CHD) in human populations although a comprehensive review of the pertinent literature on this subject in 2003 found only suggestive evidence of protection and indicated that more definitive work is needed to help understand the nature of any protective effect.

In preliminary studies in this laboratory, we have seen that dietary flaxseed oil reduced the extent of aortic atherosclerosis in genetically engineered mice. The goal of project 1 is to elucidate specific mechanisms that mediate such effects so that we may investigate their applicability in humans. We hypothesized that beneficial effects of flaxseed oil occur at least partly through the ?-linolenic acid (ALA)-induced alterations of hepatic lipid metabolism leading to a less atherogenic plasma lipoprotein profile. Additionally, we speculated that changes in fatty acid composition in cellular phospholipids due to ALA enrichment of precursor pools of fatty acids may lead to a reduction in inflammatory responses of macrophages in the artery wall. Accordingly, we have begun characterizations of the atherogenic responses to dietary flaxseed oil-induced modifications of plasma lipoprotein composition and metabolism. The B100+/+LDLr-/- mouse was chosen as the model because of its similarity in plasma lipoprotein profile to that seen in human beings. The principal cholesterol-carrying lipoprotein in the plasma of this animal is LDL containing apoB100, which is the primary candidate as the bad guy or promoter of atherosclerosis in human CHD patients. We are proposing to completely analyze the chemical composition of these lipoproteins, including the proportions and fatty acid makeup of each of the major lipid classes. We are proposing to examine the role of flaxseed oil in modifications of hepatic cholesterol metabolism that function in determination of the atherogenic changes in plasma LDL composition. Finally, we are proposing studies of the flaxseed oil-induced changes in inflammatory responses proliferated by macrophages as they may contribute to atherogenesis in this animal model.

All of the proposed endpoints are candidate mechanisms suspected of participating in the development of coronary heart disease in human patients, and the long term goal of such studies is to define the relevance of these findings to coronary heart disease prevention. The use of a relevant animal model to do invasive studies defining the molecular mechanisms involved in development of atherosclerosis should shorten the time required for installation of measures appropriate for prevention of CHD in human populations, consistent with the long term goal for this project which is prevention of CHD.