Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: The urate redox shuttle

Abstract

BACKGROUND: The topical role of uric acid and its relation to cardiovascular disease, renal disease, and hypertension is rapidly evolving. Its important role both historically and currently in the clinical clustering phenomenon of the metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), atheroscleropathy, and non-diabetic atherosclerosis is of great importance. RESULTS: Uric acid is a marker of risk and it remains controversial as to its importance as a risk factor (causative role). In this review we will attempt to justify its important role as one of the many risk factors in the development of accelerated atherosclerosis and discuss its importance of being one of the multiple injurious stimuli to the endothelium, the arterial vessel wall, and capillaries. The role of uric acid, oxidative - redox stress, reactive oxygen species, and decreased endothelial nitric oxide and endothelial dysfunction cannot be over emphasized.In the atherosclerotic prooxidative environmental milieu the original antioxidant properties of uric acid paradoxically becomes prooxidant, thus contributing to the oxidation of lipoproteins within atherosclerotic plaques, regardless of their origins in the MS, T2DM, accelerated atherosclerosis (atheroscleropathy), or non-diabetic vulnerable atherosclerotic plaques. In this milieu there exists an antioxidant - prooxidant urate redox shuttle. CONCLUSION: Elevations of uric acid > 4 mg/dl should be considered a "red flag" in those patients at risk for cardiovascular disease and should alert the clinician to strive to utilize a global risk reduction program in a team effort to reduce the complications of the atherogenic process resulting in the morbid - mortal outcomes of cardiovascular disease.

Figure 1

Metabolic syndrome: hyperuricemia. This image focuses on the "H" phenomenon consisting of the four major players in the MS: Hyperinsulinemia, Hypertension, Hyperlipidemia and the Lipotoxicity – Obesity toxicity triad, and Hyperglycemia. These players have frequently been referred to as the "deadly quartet" and the "H" phenomenon. It is important to note the central position of insulin resistance in this image and also hyperuricemia. Hyperuricemia is flanked by hyperhomocysteinemia to indicate its importance in the MS. Each of these players has its own important role and this image helps to portray the clustering effect and synergism to contribute to an overall increased oxidative – redox stress to the endothelium of the vasculature.

Figure 2

Multiple injurious stimuli to the endothelium in non-diabetic atherosclerosis and atheroscleropathy. This image portrays the anatomical relationship between the endothelium, intima, media and the adventitia. Each of these layers plays an important role in the development of accelerated atherosclerosis (atheroscleropathy) of the MS, PD, and overt T2DM. Of all the different layers the endothelium seems to play a critical and central role. It is placed at a critical location and acts as an interface with nutrients and toxic products not only at its luminal surface of musculo-elastic arteries but also at the endothelial extracellular matrix interface of the interstitium in capillary beds. The intima, sandwiched between the medial muscular layer and the endothelium, is the site of atherosclerosis, intimopathy, and the atheroscleropathy associated with MS, PD, and overt T2DM. There are multiple injurious stimuli to the endothelium including ROS and hyperuricemia. It is important to note that redox stress occurs upstream from inflammation by activating the nuclear transcription factor: NFkappa B [39]. Over time, individually and synergistically these injurious stimuli (table 1) result in the morbid – mortal vascular complications of MS, T2DM, atheroscleropathy, and non-diabetic atherosclerosis.

Figure 3

Antioxidant – prooxidant urate redox shuttle. The antioxidant – prooxidant urate redox shuttle is an important concept to understand regarding accelerated atherosclerosis. This shuttle is important in understanding the role of how the antioxidant uric acid becomes prooxidant in this environmental milieu, which results in its damaging role to the endothelium and arterial vessel wall remodeling with an elevated tension of oxidative – redox stress (ROS), accelerated atherosclerosis and arterial vessel wall remodeling.

Figure 4

Uncoupling of the eNOS reaction. It is important to understand the role of endothelial dysfunction in accelerated atherosclerosis and even more important to understand the role of eNOS enzyme uncoupling and how it relates to MS, PD, T2DM, and non-diabetic atherosclerosis. Oxygen reacts with the eNOS enzyme in which the tetrahydrobiopertin (BH₄) cofactor has coupled nicotinamide dinucleotide phosphate reduced (NAD(P)H) emzyme with L-arginine to be converted to nitric oxide (NO) and L-citrulline. When uncoupling occurs the NAD(P)H enzyme reacts with O₂ and the endothelial cell becomes a net producer of superoxide (O₂^•) instead of the protective endothelial NO. This figure demonstrates the additional redox stress placed upon the arterial vessel wall and capillaries in patients with MS, PD, and overt T2DM.