Role of Dietary Antioxidants in the Preservation of Vascular Function and the Modulation of Health and Disease

Abstract

In vascular diseases, including hypertension and atherosclerosis, vascular endothelial dysfunction (VED) occurs secondary to altered function of endothelial nitric oxide synthase (eNOS). A novel redox regulated pathway was identified through which eNOS is uncoupled due to S-glutathionylation of critical cysteine residues, resulting in superoxide free radical formation instead of the vasodilator molecule, nitric oxide. In addition, the redox sensitive cofactor tetrahydrobiopterin, BH4, is also essential for eNOS coupling. Antioxidants, either individually or combined, can modulate eNOS uncoupling by scavenging free radicals or impairing specific radical generating pathways, thus preventing oxidative stress and ameliorating VED. Epidemiological evidence and dietary guidelines suggest that diets high in antioxidants, or antioxidant supplementation, could preserve vascular health and prevent cardiovascular diseases (CVDs). Therefore, the purpose of this review is to highlight the possible role of dietary antioxidants in regulating eNOS function and uncoupling which is critical for maintenance of vascular health with normal blood flow/circulation and prevention of VED. We hypothesize that a conditioned dietary approach with suitable antioxidants may limit systemic oxidation, maintain a beneficial ratio of reduced to oxidized glutathione, and other redox markers, and minimize eNOS uncoupling serving to prevent CVD and possibly other chronic diseases.

Keywords: antioxidants; blood flow; endothelial nitric oxide synthase coupling; nitric oxide; vascular health.

Figures

Figure 1

A proposed model of how a favorable redox environment prevents vascular endothelial dysfunction and possibly the risk for cardiovascular disease in an uncontrolled and controlled redox environment. (A) Uncontrolled oxidative environment: chronic low intakes of antioxidant nutrients and dietary polyphenols/flavonoids can result in a low glutathione (GSH):GSSH ratio and a diminished capacity to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS). The oxidative burden favors S-glutathionylation (oxidation) of cysteine residues 689 and 908 in endothelial nitric oxide synthase (eNOS) (eNOS-S-SG2), and BH4 is oxidized (black with white font), leading to uncoupled eNOS, and superoxide (O2⋅−) formation. Thus, vasodilation is impaired due to loss of eNOS function with a pivotal switch from production of the vasodilator nitric oxide (NO) to the vasoconstrictor superoxide. Over time, this may contribute to vascular disease, intestinal ischemia, coronary ischemia, hypertension, diabetes, and hyperlipidemia. (B) Controlled oxidative environment: dietary flavonoids/polyphenols and antioxidant nutrients promote a thiol rich (high GSH:GSSH ratio) pool serving to scavenge ROS and RNS, thus, preventing or reversing protein S-glutathionylation (cysteine oxidation). This maintains unoxidized BH4 (silver with black font) levels and eNOS coupling, producing NO which promotes vasodilation and reduces vascular endothelium mediated inflammation/injury. This more favorable environment may over time, delay the progression to vascular disease, and other chronic disease.

Figure 2

Schematic illustration depicting the mechanism of eNOS S-glutathionylation in endothelial cells. S-glutathionylation in endothelial cells (superimposed yellow fluorescence—eNOS-S-SG) due to endothelial nitric oxide synthase (eNOS) (green—down arrow) and glutathionylated eNOS (red—down arrow) when probed with general GSH antibody. A regulatory switch happens with physiological stress (oxidative stress), often during disease conditions, where eNOS makes superoxide in its glutathionylated form (blood vessel constriction), instead of nitric oxide (blood vessel dilation) compared with normal (healthy) conditions.

Figure 3

Proposed representation of progression of endothelial function as the redox state becomes less favorable. In the healthy state coupled endothelial nitric oxide synthase (eNOS) dominates as oxidative species and free radicals are handled by the high reductive capacity from dietary antioxidants. Tetrahydrobiopterin (BH4) is present in sufficient quantities. Uncoupled eNOS is present but is transient (high coupled eNOS:uncoupled eNOS ratio), and mostly occurs in response to localized fluctuations in the redox state. As the pathology shifts to the right, uncoupled eNOS is becoming more common (lower coupled eNOS:uncoupled eNOS ratio); the redox state is less able to cope with oxidative stress; and vascular endothelial dysfunction (VED) begins. BH4 levels are reduced leading to further oxidative damage and possibly inflammation. Once progression of the disease increases (shifts to the right of the figure), uncoupled eNOS is permanent (low coupled eNOS:uncoupled eNOS ratio), BH4 levels are at their lowest, and coupled eNOS is at low levels. Now oxidative reactions dominate and VED is established, leading to CVD and other chronic conditions/diseases. Up to a certain point, before VED is established and the pathology has resulted in permanent changes, the process may be reversible with lifestyle changes and medication.