Long-term vitamin E supplementation reduces atherosclerosis and mortality in Ldlr-/- mice, but not when fed Western style diet

Atherosclerosis. 2014 Mar;233(1):196-205. doi: 10.1016/j.atherosclerosis.2013.12.006. Epub 2014 Jan 8.


Objectives: Epidemiological and experimental evidence have indicated potential health benefits of vitamin E supplementation on coronary heart disease (CHD), but several clinical trials have reported no benefit from vitamin E supplementation on CHD. We hypothesized that supplemental intake of vitamin E from an early age may prevent or retard the development and progression of atherosclerosis and CHD mortality.

Methods: To test this hypothesis, 300 Ldlr(-/-) mice were divided into groups receiving Western style high fat/cholesterol (HFHC), moderate fat/cholesterol (MFMC), or low fat/cholesterol (LFLC) diets all containing 50 IU of vitamin E. These dietary groups were further subdivided into four sub-groups (n = 25) receiving their respective diets with no vitamin E supplementation or additionally supplemented with vitamin E (500 IU/kg diet) starting at the early age of 5 wks, or 6 mo, or 12 mo. All mice remained on their assigned diets until age 18 mo. Body weight, health status and survival rate of mice were monitored and recorded. After 18 mo of dietary treatments, mice were sacrificed.

Results: Body weight was the highest in HFHC groups and the lowest in LFLC groups. Plasma concentration of cholesterol and triglycerides was high in all dietary groups, and plasma vitamin E was high in vitamin E supplemented groups. Fifty percent of mice fed Western style HFHC diet and 53% of mice fed MFMC diet survived during the 18 mo, whereas 75% of mice fed LFLC diet survived during the 18 mo dietary treatments. At the age of 18 mo, all the Ldlr(-/-) mice, regardless of dietary treatments, had several advanced atherosclerotic lesions in both aortic root and aortic tree. Within the LFLC groups, those that received vitamin E supplements from age 5 wks up to 18 mo had a significantly higher survival rate of 88% (p = 0.04) and lower mortality (12%) compared to mice that did not receive vitamin E supplements (64%). This lower mortality rate and higher survival rate coincided with significantly (p = 0.03) fewer aortic lesions in the vitamin E supplemented LFLC group (50%) compared to LFLC mice that did not receive vitamin E supplements in their diets (65%). Subjective immunohistochemical evaluation of aortic valves showed that LFLC mice that received vitamin E supplements for 18 mo had less intima media thickness compared to LFLC mice that did not receive vitamin E supplements in their diet. The LFLC mice that were supplemented with vitamin E for 18 mo had the lowest mRNA expression of inflammatory markers such as VCAM-1, MCP-1 and CD36 in samples obtained from lesion and non-lesionareas.

Conclusion: In conclusion, 500 mg vitamin E/kg diet in Ldlr(-/-) mice is not effective at reducing mortality and atherosclerosis when the diet contained high or medium levels of fat and cholesterol. However, a relatively low dose and long-term vitamin E supplementation started from an early age is effective in reducing mortality and atherosclerotic lesions in genetically prone Ldlr(-/-) mice fed LFLC diet.

Keywords: Atherosclerosis; Fatty lesion; Ldlr(−/−) mouse; Long-term supplementation; Survival; Vitamin E.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging
  • Animals
  • Atherosclerosis / mortality
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Cholesterol, Dietary / administration & dosage*
  • Diet / adverse effects*
  • Diet, High-Fat / adverse effects
  • Dietary Fats / administration & dosage*
  • Dietary Supplements
  • Lipids / blood
  • Male
  • Mice
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Vitamin E / therapeutic use*


  • Cholesterol, Dietary
  • Dietary Fats
  • Lipids
  • Receptors, LDL
  • Vitamin E