Uric acid as one of the multiple injurious stimuli to the endothelium of the arterial vessel wall and capillary

The upper 1/3 of the normal physiologic – homeostatic range (> 4 mg/dl) and abnormal elevations (> 6.5 or 7 mg/dl in men and > 6.0 mg/dl in women) in SUA definitely should be considered as one of the multiple injurious stimuli to the arterial vessel wall and capillary, which may contribute to endothelial dysfunction and arterial – capillary vessel wall remodeling through oxidative – redox stress [2,3,19] (figure 2). There are multiple injurious stimuli to the endothelium and arterial vessel wall in the accelerated atherosclerosis associated with MS and T2DM (atheroscleropathy)(figure 2). 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 injurious stimuli of the A-FLIGHT-U acronym (table 1) result in the morbid – mortal complications of MS, T2DM, atheroscleropathy, and non-diabetic atherosclerosis.

Each of these A-FLIGHT-U toxicities may be viewed as an independent risk marker – factor and is known to have a synergistic effect when acting in concert [19,21,39,42,43]. Additionally, low density lipoproteins such as LDL-cholesterol are capable of being modified and retained within the intima through a process of oxidative modification through free radicals, hypochlorous acid, peroxynitrite, and selected oxidative enzymes such as xanthine oxidase, myeloperoxidase and lipoxygenase (table 5) [19,44-50].

The simple concept that Serum uric acid (SUA) in patients with CVD, MS, T2DM, hypertension, and renal disease may reflect a compensatory mechanism to counter oxidative stress is intriguing. However, this does not explain why higher serum uric acid levels in patients with these diseases are generally associated with worse outcomes [11].

An antioxidant – prooxidant urate redox shuttle

Antioxidants may become prooxidants in certain situations [51-55]. Therefore we propose the existence of an antioxidant – prooxidant redox shuttle in the vascular milieu of the atherosclerotic macrovessel intima and the local sub endothelial capillary interstitium of the microvessel [38,51,52] (figure 3).

Serum uric acid in the early stages of the atherosclerotic process is known to act as an antioxidant and may be one of the strongest determinates of plasma antioxidative capacity [53].

However, later in the atherosclerotic process when serum uric acid levels are known to be elevated (in the upper 1/3 of the normal range >4 mg/dl and outside of the normal range >6 mg/dl in females and 6.5–7 mg/dl in males) this previously antioxidant (serum uric acid) paradoxically becomes prooxidant. This antioxidant – prooxidant urate redox shuttle seems to rely heavily on its surrounding environment such as timing (early or late in the disease process), location of the tissue and substrate, acidity (acidic – basic – or neutral ph), the surrounding oxidant milieu, depletion of other local antioxidants, the supply and duration of oxidant substrate and its oxidant enzyme. In the accelerated atherosclerotic – vulnerable plaque the intima has been shown to be acidic [54], depleted of local antioxidants with an underlying increase in oxidant stress and ROS (table 1) (table 5) and associated with uncoupling of the eNOS enzyme and a decrease in the locally produced naturally occurring antioxidant: eNO and endothelial dysfunction. This process is also occurring within the microvascular bed at the level of the capillary within various affected hypertensive and diabetic end organs [19,51,52] (figure 4).

Nitric oxide and vitamin C have each been shown to inhibit the prooxidant actions of uric acid during copper-mediated LDL-C oxidation [38,55].

The ANAi acronym

We have devised an acronym, to better understand the increase in serum uric acid synthesis within the accelerated atherosclerotic plaque termed: ANAi. A – apoptosis, N – necrosis, A – acidic atherosclerotic plaque, angiogenesis (both induced by excessive redox stress), i – inflammation, intraplaque hemorrhage increasing red blood cells – iron and copper transition metal ions within the plaque.

This acronym describes the excess production of purines: (A) adenine and (G) guanine base pairs from RNA and DNA breakdown due to apoptosis and necrosis of vascular cells in the vulnerable – accelerated atherosclerotic plaques; allowing SUA to undergo the antioxidant – prooxidant urate redox shuttle (figure 3).

Reactions involving transitional metal ions such as copper and iron are important to the oxidative stress within atherosclerotic plaques. Reactions such as the Fenton and Haber- Weiss reactions and similar reactions with copper lead to an elevated tension of oxidative – redox stress.

FENTON REACTION:

Fe²⁺ + H₂O₂ -> Fe³⁺ + OH^• + OH^-

Fe³⁺ + H₂O₂ -> Fe²⁺ + OOH^• + H⁺

HABER – WEISS REACTION:

H₂O₂ + O₂^- -> O2 + OH^- + OH

H₂O₂ + OH^- -> H₂O + O₂^- + H⁺

The hydroxyl radicals can then proceed to undergo further reactions with the production of ROS through addition reactions, hydrogen abstraction, electron transfer, and radical interactions. Additionally, copper (Cu³⁺ - Cu²⁺ - Cu¹⁺) metal ions can undergo similar reactions with formation of lipid peroxides and ROS. This makes the leakage of iron and copper from ruptured vasa vasorum very important in accelerating oxidative damage to the vulnerable accelerated atherosclerotic plaques, as well as, providing a milieu to induce the serum uric acid antioxidant – prooxidant switch within these plaques [42].

These same accelerated – vulnerable plaques now have the increased substrate of serum uric acid through apoptosis and necrosis of vascular cells (endothelial and vascular smooth muscle cells) and the inflammatory cells (primarily the macrophage and to a lesser extent the lymphocyte).

Endothelial function and endothelial nitric oxide (eNO)

The endothelium is an elegant symphony responsible for the synthesis and secretion of several biologically active molecules. It is responsible for regulation of vascular tone, inflammation, lipid metabolism, vessel growth (angiogenesis – arteriogenesis), arterial vessel wall – capillary sub endothelial matrix remodeling, and modulation of coagulation and fibrinolysis. One particular enzyme system seems to act as the maestro: The endothelial nitric oxide synthase (eNOS) enzyme and its omnipotent product: endothelial nitric oxide (eNO) (figure 2).

The endothelial nitric oxide synthase (eNOS) enzyme reaction is of utmost importance to the normal functioning of the endothelial cell and the intimal interstitium. When this enzyme system uncouples the endothelium becomes a net producer of superoxide and ROS instead of the net production of the protective antioxidant properties of eNO (table 6) (figure 4).

There are multiple causes for endothelial uncoupling in addition to hyperuricemia and the antioxidant – prooxidant urate redox shuttle: A-FLIGHT -U toxicities, ROS, T2DM, prediabetes, T1DM, insulin resistance, MS, renin angiotensin aldosterone activation, angiotensin II, hypertension, endothelin, dyslipidemia – hyperlipidemia, homocysteine, and asymmetrical dimethyl arginine (ADMA) [19,39,43].Xanthine oxidase – oxioreductase (XO) has been shown to localize immunohistochemically within atherosclerotic plaques allowing the endothelial cell to be equipped with the proper machinery to undergo active purine metabolism at the plasma membrane surface, as well as, within the cytoplasm and is therefore capable of overproducing uric acid while at the same time generating excessive and detrimental ROS [56] (figure 3,4). To summarize this section:The healthy endothelium is a net producer of endothelial nitric oxide (eNO).

The activated, dysfunctional endothelium is a net producer of superoxide (O₂^-) associated with MS, T2DM, and atheroscleropathy [43].