NIH Public Access: Author Manuscript

NIH Public Access
Author Manuscript
. Author manuscript; available in PMC 2012 July 01.
Published in final edited form as:
NIH-PA Author Manuscript
. ; 17: 656–669.
Uric Acid, Hyperuricemia and Vascular Diseases

Ming Jin1,4, Fan Yang4,†, Irene Yang4,†, Ying Yin2,4,†, Jin Jun Luo3,4, Hong Wang2,4, and
Xiao-Feng Yang2,4,*
1Department of Pathology and Laboratory Medicine, Philadelphia, PA 19140
2Department of Pharmacology and Cardiovascular Research Center, Philadelphia, PA 19140

3Department of Neurology, Philadelphia, PA 19140
4Temple University School of Medicine, Philadelphia, PA 19140
Abstract
Uric acid is the product of purine metabolism. It is known that hyperuricemia, defined as high
levels of blood uric acid, is the major etiological factor of gout. A number of epidemiological
reports have increasingly linked hyperuricemia with cardiovascular and neurological diseases.
Studies highlighting the pathogenic mechanisms of uric acid point to an inflammatory response as
the primary mechanism for inducing gout and possibly contributing to uric acid's vascular effects.
Monosodium urate (MSU) crystals induce an inflammatory reaction, which are recognized by
Toll-like receptors (TLRs). These TLRs then activate NALP3 inflammasome. MSU also triggers
neutrophil activation and further produces immune mediators, which lead to a proinflammatory
response. In addition, soluble uric acid can also mediate the generation of free radicals and
function as a pro-oxidant. This review summarizes the epidemiological studies of hyperuricemia
and cardiovascular disease, takes a brief look at hyperuricemia and its role in neurological
diseases, and highlights the studies of the advanced pathological mechanisms of uric acid and
inflammation.
Keywords
uric acid; hyperuricemia; inflammation; vascular disease; inflammasome
2. Introduction
Uric acid is the end product of nucleic acid metabolism. High levels of blood uric acid have
long been associated with gout. Gouty arthritis (gout) is a medical condition characterized
by red, tender, hot, and swollen joints caused by recurrent attacks of acute inflammatory
arthritis. The prevalence of gout in the United States has increased from 2.9 cases per 1,000
persons in 1990 to 5.2 cases per 1,000 persons in 1999 (1), due to increasing age of the
population. Men have a higher risk of developing gout than women due to higher baseline
levels of blood uric acid. Pathologically, gout is caused by an increase of blood uric acid
levels, which leads to crystal deposits in joints, tendons, and other tissues and uric acid renal
stones (2).
Recently, gout has been linked to cardiovascular disease. Epidemiological data supports the
strong association between cardiovascular disease and gout (3-5). Furthermore, multiple
*
Corresponding author: Xiao-Feng Yang, MD, PhD, FAHA, Department of Pharmacology, Temple University School of Medicine,
3420 North Broad Street, Philadelphia, PA 19140, U.S.A.; Phone: 215-707-5985; Fax: 215-707-7068; [email protected].
†Contributed equally to this work
Jin et al. Page 2
studies have also associated hyperuricemia with the precursors of cardiovascular diseases,
including hypertension, metabolic syndrome, and coronary artery disease, as well as with
closely related vascular diseases such as cerebrovascular disease, vascular dementia,
preeclampsia, and kidney disease (6-12). In 2004, a prospective cohort study showed that
hyperuricemia may be an independent risk factor for cardiovascular disease in middle aged
men (13). However, other multivariate analyses have not supported this claim (14, 15).
Although a consensus on the association of hyperuricemia with cardiovascular disease has
not been reached, these debates have motivated investigators to further determine the
mechanisms underlining uric acid and its associated diseases. Recent studies on gout have
advanced the understanding of pathological mechanisms of uric acid crystal-induced
inflammation (16-18). These mechanisms may also play a role in uric acid's link to vascular
disease. In this article, we review the relationship of hyperuricemia and vascular disease by
highlighting uric acid's role in inflammation and gout.
3. Biochemistry and Metabolism of Uric Acid

Uric acid is a heterocyclic organic compound with the formula C5H4N4O3 (7, 9-dihydro-1H-
purine-2, 6, 8(3H)-trione) and a molecular weight of 168 Daltons. Uric acid is the final
metabolic product of purine metabolism in humans, and is excreted in urine. Many enzymes
are involved in the conversion of the two purine nucleic acids, adenine and guanine, to uric
acid. Initially, adenosine monophosphate (AMP) is converted to inosine by two different
mechanisms; either first removing an amino group by deaminase to form inosine

monophosphate (IMP) followed by dephosphorylation with nucleotidase to form inosine, or
by first removing a phosphate group by nucleotidase to form adenosine followed by
deamination to form inosine. Guanine monophosphate (GMP) is converted to guanosine by
nucleotidase. The nucleosides, inosine and guanosine, are further converted to purine base,
hypoxanthine and guanine, respectively, by purine nucleoside phosphorylase (PNP).
Hypoxanthine is then oxidized to form xanthine by xanthine oxidase, and guanine is
deaminated to form xanthine by guanine deaminase. Xanthine is again oxidized by xanthine
oxidase to form the final product, uric acid (Figure 1). At physiologic pH, uric acid is a
weak acid with a pK of 5.8. Uric acid exists majorly as urate, the salt of uric acid. As urate
concentration increases in blood, uric acid crystal formation increases. The normal reference
interval of uric acid in human blood is 1.5 to 6.0 mg/dL in women and 2.5 to 7.0 mg/dL in
men. The solubility of uric acid in water is low, and in humans, the average concentration of
uric acid in blood is close to the solubility limit (6.8 mg/dL). When the level of uric acid is
higher than 6.8 mg/dL, crystals of uric acid form as monosodium urate (MSU). Studies have
found that MSU triggers the inflammation seen in gout (14-16), and may also contribute to
the pathogenesis of vascular diseases (see the section 10 for the details).
Humans cannot oxidize uric acid to the more soluble compound allantoin due to the lack of
uricase enzyme. Normally, most daily uric acid disposal occurs via the kidneys. In most
other mammals, the enzyme uricase (urate oxidase) further oxidizes uric acid to allantoin.
Uricase gene likely underwent a functional mutation during the early stages of hominoid
evolution (19). As a result, humans and several other primates have no functional uricase,
which consequently leads to higher blood uric acid levels when compared to rodents (19).
Hyperuricemia has detrimental effects for multiple organ systems. Uricase gene deficient
mice have a 10 fold increase in the serum uric acid level, and are found to have urate
nephropathy with infiltration of plasma cells, lymphocytes, and macrophages (20). More
than half of the mutant mice die before 4 weeks of age (20). On the other hand,
hyperuricemia may have some beneficial effects. Although it has been debated whether the
loss of urate oxidase was simply an evolutionary accident (21), Watanabe has suggested
that hyperuricemia maintains blood pressure during low salt intake environments, which
may have provided a survival advantage during the course of primate evolution (22).
. Author manuscript; available in PMC 2012 July 01.

NIH Public Access: Author Manuscript

Uploaded by

Copyright:

Available Formats

NIH Public Access: Author Manuscript

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

NIH Public Access: Author Manuscript

Uploaded by

Copyright:

Available Formats

NIH Public Access

Uric Acid, Hyperuricemia and Vascular Diseases

2Department of Pharmacology and Cardiovascular Research Center, Philadelphia, PA 19140

3. Biochemistry and Metabolism of Uric Acid

mechanisms; either first removing an amino group by deaminase to form inosine

. Author manuscript; available in PMC 2012 July 01.

You might also like