Beneficial effect of low ethanol intake on the cardiovascular system: possible biochemical mechanisms

Abstract

Low ethanol intake is known to have a beneficial effect on cardiovascular disease. In cardiovascular disease, insulin resistance leads to altered glucose and lipid metabolism resulting in an increased production of aldehydes, including methylglyoxal. Aldehydes react non-enzymatically with sulfhydryl and amino groups of proteins forming advanced glycation end products (AGEs), altering protein structure and function. These alterations cause endothelial dysfunction with increased cytosolic free calcium, peripheral vascular resistance, and blood pressure. AGEs produce atherogenic effects including oxidative stress, platelet adhesion, inflammation, smooth muscle cell proliferation and modification of lipoproteins. Low ethanol intake attenuates hypertension and atherosclerosis but the mechanism of this effect is not clear. Ethanol at low concentrations is metabolized by low Km alcohol dehydrogenase and aldehyde dehydrogenase, both reactions resulting in the production of reduced nicotinamide adenine dinucleotide (NADH). This creates a reductive environment, decreasing oxidative stress and secondary production of aldehydes through lipid peroxidation. NADH may also increase the tissue levels of the antioxidants cysteine and glutathione, which bind aldehydes and stimulate methylglyoxal catabolism. Low ethanol improves insulin resistance, increases high-density lipoprotein and stimulates activity of the antioxidant enzyme, paraoxonase. In conclusion, we suggest that chronic low ethanol intake confers its beneficial effect mainly through its ability to increase antioxidant capacity and lower AGEs.

Figure 1

Mechanism of cardiovascular disease. In insulin resistant state, excess aldehydes formed due to altered glucose/lipid metabolism react with proteins to form advanced glycation end products (AGEs). AGEs alter the functions of cellular proteins including vascular ion channels, and metabolic and antioxidant enzymes, with oxidative stress leading to hypertension and atherosclerosis.

Figure 2

Atherosclerotic and hypertensive effects of advanced glycation end products (AGEs) on blood vessels. AGEs act directly and via receptors of AGEs (RAGES) to alter the function of cellular proteins including calcium channels, endothelial nitric oxide synthase (eNOS), antioxidant enzyme superoxide dismutase (SOD) resulting in a decrease in NO and an increase of reactive oxygen species (ROS), cytokines, imflammation, platelet aggregation and vascular smooth muscle cell (VSMC) proliferation. AGEs and ROS also modify low density lipoprotein (LDL) increasing uptake by macrophages contributing to the formation of plaque. These alterations lead to hypertension and atherosclerosis.

Figure 3

Metabolism of high versus low concentrations of ethanol. In high concentrations, ethanol is metabolized by the microsomal ethanol oxidizing system (MEOS) system. In this reaction, reduced nicotinamide adenine dinucleotide phosphate (NADPH) is converted to oxidized nicotinamide adenine dinucleotide phosphate (NADP⁺) creating an oxidative environment. In low concentrations, ethanol is metabolized by the enzymes alcohol and aldehyde dehydrogenase producing reduced nicotinamide adenine dinucleotide (NADH) from oxidized nicotinamide adenine dinucleotide (NAD⁺) by both reactions, increasing antioxidant capacity. At the low levels produced, acetate, which is a normal metabolite of glucose and fatty acid metabolism, is further metabolized in the citric acid cycle.

Figure 4

Antioxidant activity of low ethanol. Free radicals (ROO⁻) are reduced (ROOH) by vitamins which become oxidized in the process. These vitamin radicals are reduced by nicotinamide adenine dinucleotide (NADH) which forms oxidized nicotinamide adenine dinucleotide (NAD⁺). Ethanol in low concentrations converts NAD⁺ back into NADH, via its metabolism to acetate. At this low level, acetate, which is a normal metabolite of glucose and fatty acid metabolism, is further metabolized in the citric acid cycle.

Figure 5

Mechanism of action of low ethanol.