Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis
Abstract
:1. Introduction
2. Mechanisms of Hyperuricemia
3. Epidemiology of Association between Uric Acid and Atherosclerosis
4. The Role of Hyperuricemia in the Pathogenesis of Atherosclerosis
4.1. Oxidative Stress
- ROS are produced due to the increased activity of xanthine oxidase in the metabolic process of uric acid;
- The expression and activity of NADPH oxidase increase;
- Mitochondrial ROS (mtROS) are produced due to mitochondrial injury.
4.1.1. Xanthine Oxidoreductase
4.1.2. NADPH Oxidase
4.1.3. Mitochondrial ROS
4.2. Inflammatory Signaling Pathway
4.2.1. ERK/p38 MAPK Cascade
4.2.2. AMPK
4.2.3. PI3K-Akt Pathway
4.2.4. Inflammasome
4.2.5. NO, HMGB1, RAA, ER Stress, and Mechanism of Sensing UA
5. The Effect of Therapeutic Agents for Gout on Atherosclerosis
Drugs | Study Design | Control | Participants | Number | Results |
---|---|---|---|---|---|
Allopurinol | RCT [107] | Usual therapy | Patientis with CKD (eGFR < 60 mL/min). | 113 | Allopurinol slows down the progression of renal disease and reduces risk of cardiovascular events by 71%. |
RCT [108] | Placebo | Adults with stage 3 or 4 CKD and no history of gout. | 369 | Allopurinol did not slow the decline in eGFR as compared with placebo. | |
Meta-analysis: 12 RCTs [123] | Placebo or no treatment | RCTs investigated allopurinol’s effects on endothelial function. Patients with CHF, CKD, or type 2 DM. | CHF; 197 CKD; 183 DM; 170 | Allopurinol had a benefit on endothelial function in patients with CHF and CKD but not in type 2 DM. | |
Meta-analysis: 9 RCTs [109] | Placebo or control | Patients undergoing CABG, after ACS or CHF. | 850 | Allopurinol was associated with the reduction of odds of periprocedural ACS but not with that of long-term secondary prevention of ACS. | |
Febuxostat | RCT [116] | Allopurinol | Patients with gout and cardiovascular disease. | 6190 | All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (HR for all death, 1.22; HR for cardiovascular death, 1.34). |
RCT [117] | Allopurinol | Patients were ≥60 y.o., already receiving allopurinol, and had at least one additional cardiovascular risk factor. | 6128 | Febuxostat is non-inferior to allopurinol therapy as the primary cardiovascular endpoint and not associated with an increased risk of death. | |
Xanthine oxidase inhibitor (XOI) | Meta-analysis: 81 RCTs [119] | Placebo or no treatment | RCTs comparing purine-like or non-purine XOI with placebo or no treatment (control) for a period equal or superior to 28 days in adult patients. | 10,684 (6434 pt·yr) | XOI did not significantly reduce the risk of MACE and death but reduced the risk of TCE and hypertension. |
Urate-lowering treatment (ULT) | Meta-analysis: 18 RCTs [120] | Placebo or other ULT drugs | RCTs had to report cardiovascular safety of urate-lowering treatment (allopurinol, febuxostat, pegloticase, rasburicase, probenecid, benzbromarone). | 7757 | Any ULT did not demonstrate a significant difference in any cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, or all-cause mortality. |
Colchcine | RCT [122] | Placebo | Patients suffered from MI within 30 days. | 4745 | The primary endpoint occurred at 5.5% in the colchicine group compared with 7.1% in the placebo group (HR 0.77, 95% CI 0.61–0.96). |
RCT [89] | Placebo | Patients had any evidence of coronary disease and have been in a clinically stable condition for at least 6 months. | 5522 | A primary endpoint event occurred in 6.8% in the colchicine group and 9.6% in the placebo group (HR 0.69, 95% CI 0.57–0.83). |
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Kimura, Y.; Tsukui, D.; Kono, H. Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis. Int. J. Mol. Sci. 2021, 22, 12394. https://doi.org/10.3390/ijms222212394
Kimura Y, Tsukui D, Kono H. Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis. International Journal of Molecular Sciences. 2021; 22(22):12394. https://doi.org/10.3390/ijms222212394
Chicago/Turabian StyleKimura, Yoshitaka, Daisuke Tsukui, and Hajime Kono. 2021. "Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis" International Journal of Molecular Sciences 22, no. 22: 12394. https://doi.org/10.3390/ijms222212394
APA StyleKimura, Y., Tsukui, D., & Kono, H. (2021). Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis. International Journal of Molecular Sciences, 22(22), 12394. https://doi.org/10.3390/ijms222212394