Location: Human Nutrition Research Center on Aging
Title: Long-term vitamin E supplementation reduces atherosclerosis and mortality in LDLR -/- mice, but not when fed Western style diet Authors
|Meydani, Mohsen -|
|Kwan, Paul -|
|Band, Michael -|
|Knight, Ashley -|
|Guo, Weimin -|
|Goutis, Jason -|
|Ordovas, Jose -|
Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 9, 2013
Publication Date: March 1, 2014
Citation: Meydani, M., Kwan, P., Band, M., Knight, A., Guo, W., Goutis, J., Ordovas, J. 2014. Long-term vitamin E supplementation reduces atherosclerosis and mortality in LDLR -/- mice, but not when fed Western style diet. Atherosclerosis. 233:196-205. http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.006. Interpretive Summary: Atherosclerosis, an inflammatory disease of the arteries, is the leading cause of serious illness and death from coronary heart disease (CHD) in Western countries like the U.S. Vitamin E has been investigated widely for its effect on CHD. Observational and animal studies indicate that vitamin E reduces the risks of CHD but clinical studies have thus far reported no benefit. These differing results suggest that vitamin E may not be effective once CHD is established. Since the formation of fatty deposits begins at an early age and then develops into a serious condition in middle or later life, we theorized that supplementing the diet with vitamin E at an early age may reduce or prevent fatty deposits and may prevent or slow down the development of CHD in later life. To test this theory, we used a mouse model of human atherosclerosis. Mice were divided into groups receiving high, moderate or low levels of fat and cholesterol. Within these 3 diets, mice were divided into 4 sub-groups receiving: no vitamin E or receiving vitamin E at 5 weeks, 6 months, or 12 months age. The weight, health status, and survival rate of the mice were monitored until 18 months of age. Results of the study showed that vitamin E supplementation in mice genetically prone to develop atherosclerosis did not reduce the development of fatty deposits in the blood vessels or the death rate when the diet was high in fat and cholesterol. However, a relatively low dose of vitamin E beginning at an early age along with a reduced fat and cholesterol content in the diet decreased atherosclerosis and death rate in this specific mouse model. These findings suggest that CHD is best prevented through preventive measures via a low fat/cholesterol diet and vitamin E supplementation beginning at an early age.
Technical Abstract: Epidemiological and experimental evidence indicated potential health benefits of vitamin E supplementation on coronary heart disease (CHD), but several clinical trials reported no benefit from vitamin E supplementation on CHD. We hypothesized that supplemental intake of vitamin E from early age may prevent or retard development and progression of atherosclerosis and CHD mortality. To test this hypothesis, 300 LDLR knockout mice were divided into groups receiving Western style high fat/cholesterol diet (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 groups (N equals 25) receiving respective diets supplemented with no vitamin E or additionally supplemented with vitamin E (500 IU/kg diet) started either from the early age of 5 wks, or from the age of 6 mo, or 12 mo to the age of 18 mo. Body weight, health status and survival rate of mice were monitored and recorded and after 18 mo of dietary treatments, mice were sacrificed. Body weight was the highest in HFHC groups and lowest in LFLC groups. Plasma concentration of cholesterol 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 percent of mice fed MFMC diet survived during the 18 mo, whereas 75 percent of mice fed LFLC diet survived during the 18 mo dietary treatments. At the age of 18 mo, all the LDLR knockout mice regardless of dietary treatments had several advanced atherosclerotic lesions in aortic root and aortic tree. Within the LFLC groups those received vitamin E supplement from the early age of 5 wks for 18 mo had significantly higher survival rate of 88 percent (p equals 0.04) lower mortality (12 percent) compared to mice who did not receive vitamin E supplement (64 percent). This lower mortality rate and higher survival rate was coincided with a significant (p equals 0.03) lesser aortic lesions in vitamin E supplemented LFLC group (50 percent) compared to LFLC mice who did not receive vitamin E supplement in their diets (65 percent). Subjective immunohistochemical evaluation of aortic valves showed that LFLC mice who received vitamin E supplement for 18 mo had less intima media thickness compared to those of LFLC mice who did not received vitamin E supplement in their diet. The LFLC mice who 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-lesion area. In conclusion, 500 mg vitamin E/kg diet in LDLR knockout mice is not effective to reduce 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 early age is effective in reducing mortality and atherosclerotic lesions in genetically prone LDLR knockout mice fed LFLC diet.