Effects of Dietary Amino Acids on Serum and Macrophage Atherogenicity

Recently, the investigators have been screening for anti-atherogenic or pro-atherogenic amino acids (AAs) in the macrophage model system to better understand their role in atherogenesis. The findings so far suggest that specific AAs induce selective anti-atherogenic effects (glycine, alanine, leucine and cysteine) or pro-atherogenic effects (glutamate and glutamine) in macrophages. Taking together the above previous reports with the mechanisms behind macrophage foam cell formation and atherogenesis, it is possible that AAs could be anti-atherogenic or pro-atherogenic via their mechanism of action on macrophage foam cell formation. This paradigm may serve as a basis for the development of novel cardio-protective, anti-atherogenic nutritional, or therapeutic approaches, that should be studied in human trials.

Atherosclerosis is the underlying cause of cardiovascular diseases (CVD), the major cause of death worldwide. Atherosclerosis is an inflammatory disease of the arteries in which activated macrophages are abundant in the atherosclerotic lesions. Macrophages play key roles during early atherogenesis. After differentiating from peripheral blood monocytes, the formed intimal macrophages take up oxidized/modified lipoproteins and are transformed into lipid-rich foam cells, the hallmark feature of early atherogenesis. In addition to lipoprotein uptake, lipid accumulation in macrophages can also result from alterations in cellular lipid metabolism, e.g. attenuated reverse lipid transport or enhanced rates of lipid biosynthesis. Although much progress has been made in understanding the role of different lipids (fatty acids, cholesterol, phospholipids or triglycerides) in macrophage foam-cell formation and atherosclerosis development, little is known about the potential impact of other nutrients, such as amino acids (AAs).

Previous studies have demonstrated an association between specific AAs and increased CVD risk or higher prevalence of coronary artery disease (CAD). For instance, the role of the branched chain AAs (BCAAs; valine, leucine, and isoleucine) in atherogenesis and CVD has been recently studied. Association studies showed that the plasma levels of BCAAs significantly and independently correlated with dyslipidemia and CAD. However, BCAAs were found to possess cardio-protective effects in a heart failure rat model. Specifically, leucine was reported to attenuate atherosclerosis development in the atherosclerotic apoE-deficient (apoE-/-) mice model, by improving the plasma lipid profile and by reducing systemic inflammation. Other studies have indicated the ability of some AAs to exert anti-atherogenic effects. Glycine, the simplest AA, was inversely associated with the risk of acute myocardial infarction (AMI) in patients with high apolipoprotein B (apoB) and LDL-cholesterol levels. Cysteine is an essential AA in the biosynthesis of glutathione, a key endogenous anti-oxidant known for its anti-atherogenic properties in macrophage lipid metabolism leading to the attenuation of atherosclerosis development. Cysteine analogues such as N-acetyl cysteine (NAC) or ribose cysteine were shown to be anti-atherogenic. Arginine, a basic AA, is the main precursor for nitric oxide production in the vascular endothelium. Arginine was shown to protect endothelial cells from lipid peroxidation, and to delay or reduce atheroma formation. Arginine anti-atherogenicity includes its anti-oxidant properties and its ability to improve endothelial function in CVD or overweight patients.

The aim of the proposed study is to investigate the effects of one month of supplementation with specific AAs on changes in the macrophage atherogenicity and lipid metabolism together with other risk markers of atherosclerosis development, such as serum oxidative status and lipid levels, on healthy subjects. Findings from the current proposed study may shed light on yet unknown mechanisms by which specific AAs affect atherosclerosis development and CVD risk and hence could possibly assist in the future development of anti-atherogenic strategies

Eligibility Criteria:
Inclusion Criteria:

* healthy adult males between the ages of 18-50 after signing informed consent

Exclusion Criteria:

* pregnancy, renal, pulmonary, cardiovascular or endocrinal diseases, diabetes, cancer, morbid obesity (body mass index, BMI \> 40 kg/m2), heavy smoking (\> 20 cigarettes/day), or consumption of more than two alcoholic drinks per day. Subjects from the same hospital unit or from the laboratory where this study is conducted are also excluded