Uric Acid and Cardiovascular Disease: An Update From Molecular Mechanism to Clinical Perspective

Abstract

Uric acid (UA) is the end product of purine nucleotide metabolism in the human body. Hyperuricemia is an abnormally high level of UA in the blood and may result in arthritis and gout. The prevalence of hyperuricemia has been increasing globally. Epidemiological studies have shown that UA levels are positively correlated with cardiovascular diseases, including hypertension, atherosclerosis, atrial fibrillation (AF), and heart failure (HF). Hyperuricemia promotes the occurrence and development of cardiovascular diseases by regulating molecular signals, such as inflammatory response, oxidative stress, insulin resistance/diabetes, endoplasmic reticulum stress, and endothelial dysfunction. Despite extensive research, the underlying molecular mechanisms are still unclear. Allopurinol, a xanthine oxidase (XO) inhibitor, has been shown to improve cardiovascular outcomes in patients with HF, coronary heart disease (CHD), type 2 diabetes (T2D), and left ventricular hypertrophy (LVH). Whether febuxostat, another XO inhibitor, can improve cardiovascular outcomes as well as allopurinol remains controversial. Furthermore, it is also not clear whether UA-lowering treatment (ULT) can benefit patients with asymptomatic hyperuricemia. In this review, we focus on the latest cellular and molecular findings of cardiovascular disease associated with hyperuricemia and clinical data about the efficacy of ULT in patients with cardiovascular disease.

Keywords: cardiovascular disease; clinical prospect; molecular mechanism; therapeutics; uric acid.

Figure 1

The molecular mechanisms of high UA-inducing oxidative stress, insulin resistance, endoplasmic reticulum stress, and endothelial dysfunction. (A) High UA activating the ERK/p38 signal pathway and inhibiting the Nrf2 and PI3K/Akt signal pathway, leading to an increase in the production of ROS. Increased ROS triggers IRS1/Akt phosphorylation to induce insulin resistance in cardiomyocytes. (B) High UA induces endothelial cell apoptosis and endothelial dysfunction through endoplasmic reticulum stress and the HMGB1/RAGE pathway. eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; HMGB1, high mobility group box chromosomal protein 1; NF-κB, nuclear factor κB; NO, nitric oxide; Nrf2, NF-E2-related factor 2; p-AKT, phospho-Akt; PI3K, phosphatidylinositol 3-kinase; p-IRS1, phospho-insulin receptor substrate 1; PKC, protein kinase C; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; UA, uric acid.

Figure 2

The molecular mechanisms of high UA activating NLRP3-inflammasomes and promoting macrophage M1/M2 polarization. AMPK, AMP-activated protein kinase; HIF-1α, hypoxia-inducible factor-1α; IL-1β, interleukin-1β; MAPK, mitogen activated protein kinases; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB; NLRP3, nod-like receptor protein 3; TLR, Toll-like receptors; UA, uric acid.

Figure 3

The possible molecular mechanisms of high UA promote the occurrence and development of cardiovascular diseases. High UA regulates numerous molecular signals such as inflammation, oxidative stress, insulin resistance, and endothelial dysfunction, thus affects the progression and prognosis of cardiovascular diseases including hypertension (A), atherosclerosis (B), atrial fibrillation (C) and heart failure (D). AMPK, AMP-activated protein kinase; mROS, mitochondrial ROS; mTOR, mammalian target of rapamycin; NLRP3, nod-like receptor protein 3; RAS, renin-angiotensin system; UA, uric acid.