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Recommended URIC acid's pandemics role |
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uric acid seminal article--21 pages Nutrition & Metabolism20041:10
Published: 19 October 2004
http://healthfully.org/rpc/id3.html 1/23/18 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. 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. 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. While the topicality of serum uric acid (SUA) being a risk factor
is
currently controversial [1, 2],
there is
little controversy regarding its association as a risk marker associated with
cardiovascular (CVD) and renal disease (especially in patients with
hypertension, diabetes, and heart failure). SUA seems to be a graded marker of
risk for the development of coronary heart disease (CHD) or cerebrovascular
disease and stroke compared with patients with normal uric acid levels and
especially those in the lower 1/3 of its normal physiological range [1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]….
This controversy regarding SUA being a risk factor or a risk marker
is
not as important as understanding its overall role in the association with
endothelial cell damage, dysfunction, decreased endothelial nitric oxide (eNO)
bioavailability, and how SUA interacts with other substrate toxicities and
increased reactive oxygen species (ROS)
of the A-FLIGHT-U acronym, which result in accelerated atherosclerosis
(table 1).
accelerated atherosclerosis (table 1).NEED rest of background
Table 1
A-FLIGHT-U
ACRONYM Identification of multiple metabolic toxicities and
injurious stimuli responsible for reactive oxygen species production. (figure
2)
A Angiotensin II (also induces PKC-β isoform) Amylin
(hyperamylinemia) / amyloid toxicity AGEs/AFEs
(advanced glycosylation/fructosylation endproducts) Apolipoprotein
B Antioxidant
reserve compromised Absence
of antioxidant network Aging ADMA (Asymmetrical DiMethyl Arginine) F Free fatty acid toxicity: Obesity
toxicity: Triad L Lipotoxicity – Hyperlipidemia
– Obesity toxicity: Triad I Insulin toxicity (endogenous
hyperinsulinemia-hyperproinsulinemia) Inflammation toxicity G Glucotoxicity (compounds peripheral insulin resistance)
reductive stress Sorbitol/polyol
pathway Pseudohypoxia (increased NADH/NAD ratio) H Hypertension toxicity Homocysteine
toxicity hs-CRP T Triglyceride toxicity: Obesity
toxicity: Triad U Uric Acid toxicity: Antioxidant early in physiological range
and a
conditional prooxidant late when elevated through the paradoxical
(antioxidant → prooxidant) URATE
REDOX SHUTTLE Endothelial cell dysfunction with
eNOS uncoupling, decreased eNO and increased ROS. Vulnerable atherosclerotic plaque
milieu of being acidic, proinflammatory, excess metal ions (Fe) (Cu) from
vasa vasorum rupture and red blood cell plasma membranes due to intraplaque
hemorrhage and plaque thrombus formation.
There
are certain clinical clustering groups
with increased cardiovascular risk, which have associated hyperuricemia
(table 2). Non-diabetic
patient groups with accelerated atherosclerosis, T2DM patient groups with
accelerated atherosclerosis (atheroscleropathy), congestive heart failure
patient groups with ischemic cardiomyopathy, metabolic syndrome patient groups
(with hyperinsulinemia, hypertension, dyslipidemia, impaired glucose tolerance,
and obesity), renal disease patient groups, hypertensive patient groups,
African American patient groups, patient groups taking diuretics, and patient
groups with excessive alcohol usage. Each of these clustering groups has
metabolic mechanisms that may help to explain why SUA may be elevated
(table 2). In addition to
the recurring finding of an elevated tension of oxidative- redox stress and ROS
in many of the groups is the importance of the MS and insulin resistance.
Table
2
Hyperuricemia: clinical
clusters at cardiovascular risk
GROUPS Abbreviated
Mechanisms Patients with CVD Accelerated atherosclerosis Congestive
heart failure Increased apoptosis – necrosis of
the arterial vessel wall and capillary resulting in increased purine
metabolism and hyperuricemia. Increased oxidative – redox stress Antioxidant – Prooxidant Paradox: Urate Redox
Shuttle Patients with (T2DM) Accelerated atherosclerosis (Atheroscleropathy) Acting through obesity and insulin
resistance. Accelerated atherosclerosis with
increased vascular cell apoptosis and inflammatory necrosis with increased
purine metabolism resulting in hyperuricemia and increased oxidative stress
through ischemia-reperfusion and xanthine oxidase. Additional reductive stress
associated with glucotoxicity and pseudohypoxia. Increased oxidative-redox stress Antioxidant – Prooxidant Paradox: Urate Redox
Shuttle Obesity – Insulin resistance Hyperinsulinemia – Insulin toxicity Metabolic Syndrome (figure 1): Hyperinsulinemia Hypertension Hyperlipidemia dyslipidemia,
obesity Hyperglycemia Leptin may induce hyperuricemia. Insulin increases sodium
reabsorption and is tightly linked to urate reabsorption. Increased oxidative – redox stress Antioxidant – Prooxidant Paradox: Urate Redox
Shuttle Men
and Postmenopausal females Estrogen
is uricosuric Renal
diseases Decreases
in GFR increases uric acid levels Hypertension Urate reabsorption increased in
setting of increased renal vascular resistance, microvascular disease
predisposes to tissue ischemia that leads to increased urate generation
(excess purine metabolism) and reduced excretion (due to lactate competing
with urate transporter in the proximal tubule). Increased oxidative – redox stress Antioxidant – Prooxidant Paradox: Urate Redox
Shuttle African
American Unknown
(assumed genetic causes as yet unidentified) Diuretic
use Volume
contraction promotes urate reabsorption Alcohol
use (in excess) Increases
urate generation and decreased urate excretion
The
importance of hyperuricemia and the clustering phenomenon of the metabolic
syndrome were first described by Kylin in 1923 when he described the clustering
of three clinical syndromes: hypertension, hyperglycemia, and hyperuricemia [16]. In 1988, Reaven GM
described the important central role of insulin resistance in the seminal
Banting lecture where he described Syndrome X, which has now become known as
the metabolic syndrome (MS) and/or the insulin resistance syndrome (IRS) [17]. Seven decades after
the clustering phenomenon was reported by Kylin (1993), Reaven GM and Zavaroni
I et al. suggested
that hyperuricemia be added to the cluster of metabolic and hemodynamic
abnormalities associated with insulin resistance and/or hyperinsulinemia of
Syndrome X [18].
The
four major players in the MS are hyperinsulinemia, hypertension,
hyperlipidemia, and hyperglycemia. Each member of this deadly quartet has been
demonstrated to be an independent risk factor for CHD and capable of working
together in a synergistic manner to accelerate both non-diabetic atherosclerosis
and the atheroscleropathy associated with MS, PD, and T2DM.
In
a like manner, hyperuricemia, hyperhomocysteinemia, ROS, and highly sensitive
C- reactive protein (hsCRP) each play an important role in expanding the
original Syndrome X described by Reaven in the atherosclerotic process. The
above quartet does not stand alone but interacts in a synergistic manner
resulting in the progression of accelerated atherosclerosis and arterial vessel
wall remodeling along with the original players and the A-FLIGHT-U toxicities
(table 1). The MS of clinical
clustering has been renamed multiple times over the past 16 years indicating
its central importance to cardiovascular disease and was included in the recent
National Cholesterol Educational Program – Adult Treatment Panel III (NCEP ATP
III) clinical guidelines in order to assist the clinician in using this
important tool to evaluate additional cardiovascular risk [16, 17, 18, 19].
Insulin,
proinsulin, and amylin
individually and synergistically activate the renin – angiotensin system (RAS)
with subsequent increase in Ang II. Ang II is the most potent endogenous
inducer of NAD(P)H oxidase, increasing NAD(P)H, which increases vascular –
intimal reactive oxygen species (ROS) and superoxide (O2-•)
[19, 20]. There are many deleterious
effects of hyperinsulinemia in addition to its being responsible for sodium,
potassium, water, and urate retention in proximal kidney (table 3) [21].
Table 3
Deleterious
effects of hyperinsulinemia (HI)
1. HI,
hyperproinsulinemia, and hyperamylinemia synergistically activate RAS with
subsequent increase in Ang II, renin, and aldosterone. 2. HI
promotes Na+ and H2O
retention, which increases blood
volume and pressure. In turn this activates the reabsorption of uric acid
resulting in elevation of SUA. In turn increased SUA has been shown to
increase tubular reabsorption of Na+. 3. HI
increases membrane cation-transport increasing intracellular Ca++, which
increases tone and pressure. 4. HI
activates the sympathetic nervous system. 5. HI
stimulates vSMC proliferation and migration and remodeling. 6. HI
increases the number of AT-1 receptors. 7. HI
creates cross talk between the insulin receptor and AT-1 receptor, resulting
in a more profound Ang II effect. 8 HI
promotes PI3 kinase Akt-MAP kinase Shunt. Impairing the metabolic (PI3
kinase-AKT pathway while promoting the MAPkinase remodeling pathway. 9. HI
induces Ang II, which promotes the MAP kinase pathway and remodeling. 10. HI
induces Ang II, which is the most potent stimulus for production of NAD(P)H
oxidase with reactive oxygen species generation (superoxide production) and
resultant vascular oxidative stress.
Hypertension
is strongly associated with hyperuricemia. SUA levels are elevated in
hypertension and are present in 25% of untreated hypertensive subjects, 50% of
subjects taking diuretics, and greater than 75% of patients with malignant
hypertension [22]. Potential mechanisms
involved with the association of hyperuricemia and hypertension include the
following: 1. Decreased renal blood flow (decreased GFR) stimulating urate
reabsorption, 2. Microvascular (capillary) disease resulting in local tissue
ischemia. 3. Ischemia with associated increased lactate production that blocks
urate secretion in the proximal tubule and increased uric acid synthesis due to
increased RNA-DNA breakdown and increased purine (adenine and guanine)
metabolism, which increases uric acid and ROS through the effect of xanthine
oxidase (XO). 4. Ischemia induces increased XO production and increased SUA and
ROS. These associations with ischemia and XO induction may help to understand
why hyperuricemia is associated with preeclampsia and congestive heart failure. Because
endothelial dysfunction, local oxidant generation, elevated circulating cytokines,
and a proinflammatory state are common in patients with cardiovascular disease
and hypertension there is an increased level of oxidative – redox stress within
vascular tissues. Oxidative – redox stress results in impaired
endothelium-dependent vasodilation with quenching of endothelial nitric oxide
(eNO) and allows the endothelium to become a net producer of ROS specifically
superoxide as the endothelial nitric oxide synthase (eNOS) enzyme uncouples to
produce superoxide instead of eNO. This similar mechanism applies equally well
to that associated with type 2 diabetes and congestive heart failure [11, 19]. It is important to
note that allopurinol and oxypurinol (XO inhibitors) are capable of reversing
the impaired eNO production in both heart failure [23, 24, 25] and type 2 diabetes
mellitus (T2DM) [26]. Lin
KC et al.
were able to demonstrate that blood pressure levels were predictive for
cardiovascular disease incidence synergistically with serum uric acid level [27]. Two separate
laboratories have demonstrated the development of systemic hypertension in a
rat model of hyperuricemia developed with a uricase inhibitor (oxonic acid)
after several weeks of treatment [28, 29]. This hypertension was
associated with increased renin and a decrease in neuronal nitric oxide
synthase in the juxtaglomerular apparatus. Prevention of this hypertension was
accomplished by an ACE inhibitor and to a lesser extent L-arginine. These
findings indicate an interacting role of the renin- angiotensin system and the
NOS enzyme. Hypertension, neural nitric oxide synthase (nNOS) and renin changes
were also prevented by maintaining uric acid levels in the normal range with
allopurinol or benziodarone (a uricosuric). These
above models have provided the first challenging evidence that uric acid may
have a pathogenic role in the development of hypertension, vascular disease,
and renal disease [11]. Obesity
has reached epidemic proportions in the past decade and represents one of the
confounding factors associated with the MS and T2DM [19, 30] (figure 1). Hyperuricemia
has been associated
with increasing body mass index (BMI) in recent studies and are even apparent
in the adolescent youth [30, 31, 32, 33]. 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. Leptin
levels are elevated and associated with insulin resistance in MS and early
T2DM. Bedir A et al. have recently
discussed the role of leptin as possibly
being a regulator of SUA concentrations in humans and even suggested that
leptin might be one of the possible candidates for the missing link between
obesity and hyperuricemia [34]. Furthermore,
hypertriglyceridemia and free fatty acids are related to hyperuricemia
independently of obesity and central body fat distribution [30, 33] (table 1: (T): Triglyceride
toxicity and (F): Free fatty acid toxicity). Glucotoxicity
places an additional burden of redox stress on the arterial vessel wall and
capillary endothelium. Hyperglycemia induces both an oxidative stress (glucose
autoxidation and advanced glycosylation endproducts (AGE) – ROS oxidation
products) and a reductive stress through pseudohypoxia with the accumulation of
NADH and NAD(P)H in the vascular intima [19, 35, 36]. This redox stress
consumes the
natural occurring local antioxidants such as: SOD, GPX, and catalase
(table 4). Once these local intimal
antioxidants are depleted uric acid can undergo the paradoxical antioxidant –
prooxidant switch or the urate redox shuttle [37, 38] Table 4 Antioxidants:
enzymatic – nonenzymatic inactivation of free radicals. ENZYMATIC
ANTIOXIDANTS SUPER OXIDE DISMUTASE (SOD) Reactions catalyzed: [O2- +
SOD → H2O2 +
O2] Various
isoforms: ecSOD (extracellular); Mn-SOD (mitochondrial); Cu/Zn-SOD
(intracellular) CATALASE – Location: peroxisome. Reaction
catalyzed: [2 H2O2 +
catalase → 2 H2O + O2] GLUTATHIONE PEROXIDASE – Location:
mitochondrion, cytosol, and systemic circulation. Glutathione (GSH or
glutamyl-cysteinyl-glycine tripeptide): the reduced -SH of GSH is oxidized to
disulfide GSSG. Glutathione peroxidase-catalyzed
reation: [GSH + 2 H2O2 →
GSSG + H2O + O2] Glutathione
reductase-catalyzed reaction: [GSSG → GSH] at the expense of [NADH → NAD+]
and/or [NAD(P)H → NAD(P)+] ENZYMATIC
– NONENZYMATIC INACTIVATION OF FREE RADICALS. NITRIC OXIDE SYNTHASE Location:
membrane. Isoforms: eNOS
(endothelial): good nNOS
(neuronal): good iNOS
(inducible-inflammatory): bad O2- and nitric oxide (NO) are
consumed in this process with the creation of reactive nitrogen species
(RNS). O2- + NO → ONOO-(peroxynitrite) +
tyrosine → nitrotyrosine. Nitrotyrosine reflects redox stress
and leaves a measurable footprint. NO the good; O2• the
bad; ONOO- the ugly * NONENZYMATIC
ANTIOXIDANTS Vitamins (A, C, and E): Thiols: Sulfhydryl (-SH)-containing
molecules. Albumin: Is an antioxidant because
of it is a thiol-containing macromolecule. Apoproteins: Ceruloplasmin and
transferrin. Bind copper and iron in forms, which cannot participate in the
Fenton reaction. Uric acid: Early on
in the atherosclerotic process in physiologic ranges: antioxidant. PARADOX: Late in
elevated range prooxidant with loss of supporting antioxidants above and in a
milieu of oxidative – redox stress within the atherosclerotic intima. In MS,
T2DM and advanced vulnerable atherosclerotic plaques SOD, Catalase, and GPX
are depleted. The Urate Redox Shuttle. PARADOX: antioxidants
may become prooxidant in a certain milieu. * Beckman JS and Koppenol WH
[1996] Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and
ugly. Am J Physiol 271(5 Part 1): C1424–C1437 A
direct relation between homocysteine levels
and SUA levels is known to occur in patients with atherosclerosis. Not only do
these two track together (possibly reflecting an underlying elevated tension of
redox stress) but also may be synergistic in creating an elevated tension of
redox stress, especially in the rupture prone, vulnerable atherosclerotic
plaque with depletion of local occurring antioxidants [39, 40, 41] (figure 1). Non-diabetic
atherosclerosis and
atheroscleropathy (accelerated atherosclerosis associated with MS, prediabetes,
and T2DM) are each impacted with the elevation of uric acid [42, 43]. In
MS and T2DM there is an observed increased
thrombogenecity, hyperactive platelets, increased PAI-1 (resulting in impaired
fibrinolysis), and increased fibrinogen in the atherosclerotic milieu
associated with the dysfunctional endothelial cell. Additionally, the
vulnerable atherosclerotic plaque includes increased tissue factor, which
increases the potential for thrombus formation when the plaque ruptures and
exposes its contents to the lumen [19, 42, 43]. 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. 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. 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, 45, 46, 47, 48, 49, 50]. Table 5 Origin, enzymatic pathways of reactive oxygen
species, and their oxidized products. [Origin and Location] Enzymatic Pathways: [ROS] Potent Oxidants: [Products] Oxidized lipids and proteins: Mitochondrial Respiratory Chain O2• -OH• Oxidized
lipids, proteins, nucleic acids, and autoxidation byproducts Inflammatory Macrophage Membranous NAD(P)H Oxidase O2• -OH• H2O2 Advanced lipoxidation endproducts
(ALE) ortho o-tyrosine meta m-tyrosine Granular Myeloperoxidase (MPO) Hypochlorous acid HOCL Tyr (Tyrosine) NO2 3-Chlorotyrosine di-Tyrosine NO2-(Nitrotyrosine) Macrophage Nitric Oxide Synthase (iNOS) Inducible (iNOS) Large
bursts – uncontrolled ONOO• NO2-(Nitrotyrosine) Endothelial
Cell Nitric Oxide Synthase (NOS) Constitutive (cNOS) eNOS → NO nNOS → NO Small
bursts – controlled NO + O 2 • →
ONOO• ONOO• NO2-(Nitrotyrosine) NO2-(Nitrotyrosine) eNOS-derived
NO NO The
GOOD * Natural-occurring,
local-occurring, chain-breaking, antioxidant Superoxide O 2 • The
BAD * Toxic
effects of ROS on proteins, lipid, nucleic acids Peroxynitrite ONOO • The
UGLY * Toxic
effects of ROS on proteins, lipid, nucleic acids Hypochlorous
acid HCLO The
UGLY * Toxic
effects of ROS on proteins, lipid, nucleic acids Restoration of eNO Via
the eNOS reaction Antioxidant Antioxidant Prevention
of the toxic effects of ROS * Beckman JS and Koppenol WH [1996] Nitric
oxide, superoxide,
and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271(5 Part 1):
C1424–C1437 The
simple concept that 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 SUA levels in patients
with these diseases are generally associated with worse outcomes [11]. |
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Antioxidants
may become
prooxidants in certain situations [51, 52, 53, 54, 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). 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. SUA
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 SUA 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 (SUA)
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). 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. 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]. We
have devised an acronym, to better understand the increase in SUA 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: Fe 2+ +
H 2 O 2 →
Fe 3+ +
OH • +
OH - Fe 3+ +
H 2 O 2 →
Fe 2+ +
OOH • +
H + HABER
– WEISS REACTION: H 2 O 2 +
O 2 - →
O2 + OH - +
OH H 2 O 2 +
OH - →
H 2 O
+ O 2 - +
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 SUA antioxidant – prooxidant switch within
these plaques [42]. These
same accelerated – vulnerable plaques now have the increased substrate of SUA
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). 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). Table 6 The positive effects of eNOS and eNO • Promotes vasodilatation of vascular smooth muscle. •
Counteracts smooth muscle cell proliferation. •
Decreases platelet adhesiveness. •
Decreases adhesiveness of the endothelial layer to monocytic WBCs (the
"teflon effect"). •
Anti-inflammatory effect. •
Anti-oxidant effect. It scavenges reactive oxygen species locally, and acts
as a chain-breaking antioxidant to scavenge ROS. •
Anti-fibrotic effect. When NO is normal or elevated, MMPs are quiescent;
conversely if NO is low, MMPs are elevated and active. MMPs
are redox sensitive. •
No inhibits prooxidant actions of uric acid during copper-mediated LDL
oxidation. •
NO has diverse anti-atherosclerotic actions on the arterial vessel wall
including antioxidant effects by direct scavenging of ROS – RNS acting as
chain-breaking antioxidants and it also has anti-inflammatory effects. 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]. Uric
acid and highly sensitive C reactive protein (hsCRP) each now share a respected
inclusion as two of the novel risk markers – risk factors associated with the
metabolic syndrome. It is not surprising that these two markers of risk track
together within the MS. If there is increased apoptosis and necrosis of
vascular cells and inflammatory cells in accelerated – vulnerable
atherosclerotic plaques as noted in the above section then one would expect to
see an increase in the metabolic breakdown products of RNA and DNA with
arginine and guanine to its end product of uric acid. SUA elevation may indeed
be a sensitive marker for underlying vascular inflammation and remodeling
within the arterial vessel wall and capillary interstitium. Is
it possible that SUA levels could be as similarly predictive as hsCRP since it
is a sensitive marker for underlying inflammation and remodeling within the
arterial vessel wall and the myocardium [57]. Should
the measurement of SUA be part of the national cholesterol educational program
adult treatment panel III and future IV (NCEP ATPIII or the future NCEP ATPIV)
clinical guidelines (especially in certain ethnic groups such as females and in
the African Americans)? Uric
acid is known to induce the nuclear transcription factor (NF-kappaB) and
monocyte chemoattractant protein-1 (MCP-1) [58]. Regarding TNF alpha it
has been shown that SUA levels significantly correlate with TNF alpha
concentrations in congestive heart failure and as a result Olexa P et al. conclude that SUA may
reflect the severity of systolic dysfunction and the activation of an
inflammatory reaction in patients with congestive heart failure [59]. Additionally, uric
acid also stimulates human mononuclear cells to produce interleukin-1 beta,
IL-6, and TNF alpha [11]. Tamakoshi
K et al.
have shown a statistically significant positive correlation between CRP and
body mass index (BMI), total cholesterol, triglycerides, LDL-C, fasting
glucose, fasting insulin, uric acid, systolic blood pressure, and diastolic
blood pressure and a significant negative correlation of CRP with HDL-C in a
study of 3692 Japanese men aged 34–69 years of age. They conclude that there
are a variety of components of the MS, which are associated with elevated CRP
levels in a systemic low-grade inflammatory state [60]. CRP
and IL-6 are important confounders in the relationship between SUA and overall
mortality in elderly persons, thus when evaluating this association the
potential confounding effect of underlying inflammation and other risk factors
should be considered [61]. Hyperuricemia
can be the consequence of increased uric acid production or decreased
excretion. Any cause for decreased glomerular filtration, tubular excretion or
increased reabsorption would result in an elevated SUA. Increased SUA has been found
to predict the development of renal insufficiency in individuals with normal
renal function [11]. In T2DM hyperuricemia
seems to be associated with MS and with early onset or increased progression to
overt nephropathy, whereas hypouricemia was associated with hyperfiltration,
and a later onset or decreased progression to overt nephropathy [62]. An elevated SUA could
be advantageous information for the clinician when examining the global picture
of T2DM in order to detect those patients who might gain from more aggressive
global risk reduction to delay or prevent the transition to overt nephropathy.
Elevated SUA contributes to endothelial dysfunction and increased oxidative
stress within the glomerulus and the tubulo-interstitium with associated
increased remodeling fibrosis of the kidney and as noted earlier in this
discussion to be pro-atherosclerotic and proinflammatory. This would have a
direct effect on the vascular supply affecting macrovessels, particularly the
afferent arterioles. The glomeruli would be affected also through the effect of
uric acid on the glomerular endothelium with endothelial dysfunction due to
oxidative – redox stress and result in glomerular remodeling. SUA's effect on
hypertension would have an additional affect on the glomeruli and the
tubulo-interstitium with remodeling changes and progressive deterioration of
renal function. Increased ischemia – ischemia reperfusion would activate the
xanthine oxidase mechanism and contribute to an increased production of ROS
through H2O2 generation
and oxidative stress within
the renal architecture with resultant increased remodeling. Hyperuricemia could
increase the potential for urate crystal formation and in addition to elevated
levels of soluble uric acid could induce inflammatory and remodeling changes
within the medullary tubulo-interstitium. A
recent publication by Hsu SP et al. revealed
a J-shaped curve association with SUA levels and
all-cause mortality in hemodialysis patients [63]. They were able to
demonstrate that decreased serum albumin, underlying diabetic nephropathy, and
those in the lowest and highest quintiles of SUA had higher all-cause
mortality. It is interesting to note that almost all of the large trials with
SUA and cardiovascular events have demonstrated this same J shaped curve
regarding all-cause mortality with the nadir of risk occurring in the second
quartile [11]. Johnson
RJ et al.
have speculated that the increased risk for the lowest quartile reflects a
decreased antioxidant activity, while the increased risk at higher levels
reflects the role of uric acid in inducing vascular disease and hypertension
through the mechanism of the previously discussed antioxidant prooxidant urate
redox shuttle. This would suggest that treatment with xanthine oxidase
inhibitors (allopurinol) should strive to bring levels to the 3–4 mg/dl range
and not go lower [11]. While
it is not within the scope of this review to discuss this important topic with
an in- depth examination, it is important to discuss some prevailing concepts
and provide some clinical nutritional guidelines for hyperuricemia (table 8). Table 8 Nutritional guidelines for hyperuricemia Obesity Caloric restriction to induce weight loss in order to
decrease insulin resistance of the MS. Exercise to aid in weight reduction by increased energy
expenditure, also to increase eNOS and eNO, as well as, increase HDL-C with
its antioxidant – anti-inflammatory effects. Both will result in REDOX
STRESS REDUCTION Alcohol Avoidance and or moderation.
Especially beer with the increased purines from hops and barley. Also improve
the liver antioxidant potential. REDOX
STRESS REDUCTION Low
purine diet (moderation) Moderation in meats and seafood's,
especially shrimp and barbeque ribs (all you can eat specials). Vegetables and fruits higher in
purine should not be completely avoided as they provide fiber and naturally
occurring antioxidants. Lists should be provided to
demonstrate the vegetables and fruits that are higher in purines to allow
patients healthier choices REDOX
STRESS REDUCTION Fiber Emphasize the importance of fiber in
the diet as fiber helps to bind excess purines in the gastrointestinal track. REDOX
STRESS REDUCTION Moderation is the key element in any
diet approaching hyperuricemia. The nutritional "gold standard" for
the treatment of hyperuricemia has been "the low purine diet". This
traditional diet has recently come into question as it may limit the intake of
high purine vegetables and fruits. Vegetables and fruits are important for the
fiber they supply in addition to naturally occurring antioxidants. Recently, of
greater importance is controlling obesity through generalized caloric
restriction and increased exercise to combat the overnutrition and under-exercise
of our modern-day society, as well as, controlling the consumption of alcohol [64]. Nutritional support by the nutritionist
and the diabetic educator (an integral part of the health care team) is of
utmost importance when dealing with the metabolic syndrome, T2DM, and the
cardiovascular atherosclerotic afflicted patients in order to obtain global
risk reduction, because we are what we eat. From a clinical
standpoint,
hyperuricemia should alert the clinician to an overall increased risk of
cardiovascular disease and especially those patients with an increased risk of
cardiovascular events. Hyperuricemia should therefore be a "red flag"
to the clinician to utilize a team effort in achieving an overall approach to
obtain a global risk reduction program through the use of the RAAS acronym
(table 7). Table 7 The RAAS Acronym: GLOBAL RISK REDUCTION R Reductase inhibitors (HMG-CoA).
Decreasing modified LDL-cholesterol, i.e., oxidized, acetylated
LDL-cholesterol. Decreasing triglycerides and increasing HDL-cholesterol. Improving endothelial cell
dysfunction. Restoring the abnormal Lipoprotein fractions. Thus,
decreasing the redox and oxidative stress to the arterial vessel wall and
myocardium. Redox
stress reduction A AngII inhibition or receptor
blockade: ACEi-prils.
ARBs-sartans. Both
inhibiting the effect of
angiotensin-II locally as well as systemically. Affecting hemodynamic stress
through their antihypertensive effect as well as the deleterious effects of
angiotensin II on cells at the local level – injurious stimuli -decreasing
the stimulus for O2• production. Decreasing the
A-FLIGHT toxicities. The positive effects on microalbuminuia and delaying the
progression to end stage renal disease. Plus the direct-indirect antioxidant
effect within the arterial vessel wall and capillary. Antioxidant effects. Aspirin antiplatelet,
anti-inflammatory effect on the diabetic hyperactive platelet. Adrenergic
(non-selective blockade) in addition to its blockade of
prorenin → renin conversion. Amlodipine –
Felodipine with calcium channel blocking antihypertensive effect, in addition
to their direct antioxidant effects. Redox
stress reduction A Aggressive
control of diabetes to
HbA1c of less than 7. This
usually requires combination therapy with the use of insulin secretagogues,
insulin sensitizers (PPAR-gamma agonists), biguanides, alpha-glucosidase
inhibitors, and ultimately exogenous insulin. Decreasing modified LDL cholesterol,
i.e., glycated-glycoxidated LDL cholesterol. Improving endothelial cell
dysfunction. Also decreasing glucotoxicity and the oxidative-redox stress to
the intima and pancreatic islet. Aggressive
control of blood pressure, which usually requires combination
therapy, including thiazide diuretics to attain JNC 7 guidelines. Aggressive
control of homocysteine with folic acid with its
associated additional positive effect on re-coupling the eNOS enzyme reaction
by restoring the activity of the BH4 cofactor to run the eNOS
reaction via a folate shuttle mechanism and once again produce eNO. Aggressive
control of uric acid levels
with xanthine oxidase
inhibitors (allopurinol and oxypurinol) should be strongly considered in view
of the prevailing literature in order to achieve more complete: Global Risk
Reduction Redox
stress reduction S Statins. Improving
plaque stability (pleiotropic effects) independent of cholesterol lowering.
Improving endothelial cell dysfunction. Moreover, the direct/indirect
antioxidant anti-inflammatory effects within the islet and the arterial
vessel wall promoting stabilization of the unstable, vulnerable islet and the
arterial vessel wall. Style. Lifestyle
modification (weight loss, exercise, and change eating habits). Stop
Smoking. Redox
stress reduction SUA
may or may not be an independent risk factor especially since its linkage to
other risk factors is so strong, however there is not much controversy
regarding its role as a marker of risk, or that it is clinically significant
and relevant. Regarding
the MS and epidemiologic evaluations: A multivariate model could well eliminate
hyperuricemia as an independent risk factor even if it were contributing to the
overall phenotypic risk of the syndrome. Additionally, we must remember that it
was Reaven that called for the inclusion of hyperuricemia to Syndrome X we now call
MS – insulin resistance syndrome -IRS in 1993 [18]. A
quote by Johnson RJ and Tuttle KR is appropriate for the concluding remarks: "The
bottom line is that measuring uric acid is a useful test for the clinician, as
it carries important prognostic information. An elevation of uric acid is
associated with an increased risk for cardiovascular disease and mortality,
especially in women" [64]. |
