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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #208636
Title: Dietary homocysteine promotes atherosclerosis in apoE-deficient mice by inducing scavenger receptors expression

Author
item THAMPI, PRAJITHA - ACNC/UAMS
item STEWART, BRADFORD - ACNC/ACH
item JACOB, LIJA - BOSTON MEDICAL CENTER
item MELNYK, STEPAN - UAMS/DEPT. OF PEDS
item HENNINGS, LEAH - UAMS/PATHOLOGY
item NAGARAJAN, SHANMUGAM - ACNC/UAMS

Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/4/2007
Publication Date: 4/7/2008
Citation: Thampi, P., Stewart, B.W., Jacob, L., Melnyk, S.B., Hennings, L.J., Nagarajan, S. 2008. Dietary homocysteine promotes atherosclerosis in apoE-deficient mice by inducing scavenger receptors expression. Atherosclerosis. 197(2):620-629.

Interpretive Summary: Animal protein is rich in the amino acid methionine. In the body methionine is broken down to homocysteine (Hcy). Normally, Hcy is used by the body and this process needs vitamin B. Food with less vitamin B, more fat and animal protein is considered unhealthy, and results in high blood levels of Hcy. Too much Hcy in blood is harmful. It causes walls of blood vessels to thicken, a heart disease called atherosclerosis. It is not known how Hcy causes atherosclerosis. We used an apoE gene knockout mouse model to answer this question. These mice have high levels of bad cholesterol in blood. On a normal diet these mice develop atherosclerosis at an early age. These mice were fed Hcy from four weeks of age. They developed atherosclerosis even earlier than apoE knockout mice on normal diet. Scavenger receptors are proteins found on the surface of the cells. Some factors can change the form of bad cholesterol. This form of bad cholesterol makes use of scavenger receptors to enter the cells of the blood vessels. These cells have a spongy look and are called foam cells. Results from this study show that high levels of Hcy in blood cause levels of scavenger receptors to rise in apoE mice fed Hcy. High levels of scavenger receptors help form more foam cell and cause atherosclerosis in these mice. This study shows how high levels of Hcy can cause atherosclerosis and, therefore, it is very important to keep blood levels of homocysteine low to have a fit and strong heart. The diet should be rich in vitamin B, low in fat, and low in animal protein to maintain a healthy heart.

Technical Abstract: Elevated plasma homocysteine (Hcy) levels have been recognized as an independent risk factor for cardiovascular and cerebrovascular diseases. However, the causative mechanisms have not been delineated. Scavenger receptors such as scavenger receptor-AI/II (SR-A), CD36, and lectin-like oxidized LDL receptor-1 (LOX-1)-mediated uptake of oxidized-LDL (oxLDL) have been shown to play a pivotal role in foam cell formation, an early event in atherosclerosis. We hypothesized that atherogenic effects of Hcy may be mediated via regulating expression of scavenger receptor(s). We have tested this hypothesis using an atherosclerosis-prone apolipoprotein E knockout (apoE-/-) mouse model. ApoE-/- female mice were fed normal rodent chow (NC) diet or NC with Hcy either in the pelleted diet (9 g/kg) or supplemented in drinking water (0.9 g/L). In both approaches, plasma total cholesterol, triglycerides, HDL, and LDL showed no significant change between the groups. However, Hcy-fed mice showed increased fatty streak lesions in aortic sinus/root compared to NC group. Similar findings were observed in the enface analysis of the descending aorta. To determine whether Hcy-mediated progression of fatty streak lesions was dependent on either oxLDL generation and/or expression of scavenger receptor(s), plasma oxLDL levels and expression of CD36 and LOX-1 in the aortic lesions were analyzed. Interestingly, circulating oxLDL levels, and CD36 and LOX-1 expression in aortic lesions were elevated in Hcy-fed groups compared to control. These novel findings suggest that Hcy exerts its atherogenic effect in part by elevating the levels of oxLDL and expression of scavenger receptors in aortic lesions.