Dietary flaxseed inhibits atherosclerosis in the LDL receptor-deficient mouse in part through antiproliferative and anti-inflammatory actions

Chantal M. C. Dupasquier, Elena Dibrov, Annette L. Kneesh, Paul K. M. Cheung, Kaitlin G. Y. Lee, Helen K. Alexander, Behzad K. Yeganeh, Mohammed H. Moghadasian, Grant N. Pierce

Research output: Contribution to journalArticlepeer-review

Abstract

Dietary flaxseed has been shown to have potent antiatherogenic effects in rabbits. The purpose of the present study was to investigate the antiatherogenic capacity of flaxseed in an animal model that more closely represents the human atherosclerotic condition, the LDL receptor-deficient mouse (LDLrKO), and to identify the cellular mechanisms for these effects. LDLrKO mice were administered a regular diet (RG), a 10% flaxseed-supplemented diet (FX), or an atherogenic diet containing 2% cholesterol alone (CH) or supplemented with 10% flaxseed (CF), 5% flaxseed (CF5), 1% flaxseed (CF1), or 5% coconut oil (CS) for 24 wk. LDLrKO mice fed a cholesterol-supplemented diet exhibited a rise in plasma cholesterol without a change in triglycerides and an increase in atherosclerotic plaque formation. The CS mice exhibited elevated levels of plasma cholesterol, triglycerides, and saturated fatty acids and an increase in plaque development. Supplementation of the cholesterol-enriched diet with 10% (wt/wt) ground flaxseed lowered plasma cholesterol and saturated fatty acids, increased plasma ALA, and inhibited plaque formation in the aorta and aortic sinus compared with mice fed a diet supplemented with only dietary cholesterol. The expression of proliferating cell nuclear antigen (PCNA) and the inflammatory markers IL-6, mac-3, and VCAM-1 was increased in aortic tissue from CH and CS mice. This expression was significantly reduced or normalized when flaxseed was included in the diet. Our results demonstrate that dietary flaxseed can inhibit atherosclerosis in the LDLrKO mouse through a reduction of circulating cholesterol levels and, at a cellular level, via antiproliferative and anti-inflammatory actions. it is becoming increasingly evident that atherosclerotic heart disease is largely attributable to factors that can be altered or prevented by lifestyle modification. Yusuf et al. (54) recently reported that >90% of heart disease can be influenced through behavior modifications such as nutritional interventions, cessation of smoking, and regular exercise. Nutritional recommendations have recently promoted the increased need to consume omega-3 fatty acids to provide cardioprotection against ischemic heart disease and significantly reduce the incidence of myocardial infarcts and stroke (19, 24, 33). The most common way to consume omega-3 fatty acids has been in the form of marine oils like fish. Recently, flaxseed has been identified as a significant alternative source of omega-3 (n-3) fatty acids (19). Flaxseed is one of the richest sources of α-linolenic acid (ALA). ALA has been identified in several epidemiological trials as having significant beneficial effects versus heart disease (11, 12, 14, 21, 26). However, the data have been indirect, and the mechanism of action for this cardioprotection is unclear. Dietary flaxseed is also a rich source of soluble and insoluble fibers and the lignan secoisolariciresinol diglucoside (SDG). Inclusion of flaxseed or one of its derived components in the diet in animal studies has shown that flaxseed can inhibit arrhythmogenesis during ischemia-reperfusion (1), inhibit atherogenesis (39–43), and protect against vascular dysfunction during hypercholesterolemic conditions (15). Although these studies strongly support the argument that dietary flaxseed is an important antiatherogenic agent, all of these studies have used the cholesterol-fed rabbit as the model of human atherosclerotic disease. This animal model is not an ideal representation of the human atherosclerotic process. Genetically manipulated mouse models of atherosclerotic disease such as the LDL receptor-deficient (LDLrKO) mouse more closely mimic the human condition (48, 52). The LDLrKO mouse is also considered a superior model for use in dietary intervention trials compared with other mouse models, because the LDLrKO mouse only develops diet-induced atherosclerotic lesions, as opposed to the spontaneous atherosclerotic development observed in, for example, the ApoE receptor-deficient mouse (51). It is important to evaluate the effects of flaxseed in an animal model that mimics the human condition as closely as possible before costly human trials are undertaken. The purpose of this study, therefore, was to assess the antiatherogenic effects of three concentrations of dietary flaxseed in LDLrKO mice and to determine the mechanism of action of flaxseed at a cellular level.
Original languageEnglish
Pages (from-to)H2394-H2402
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number4
DOIs
Publication statusPublished - 1 Oct 2007

Keywords

  • linseed
  • nutrition
  • a-linolenic acid
  • cardiovascular disease
  • inflammation

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