Hyperuricemia promotes the progression of atherosclerosis by activating endothelial cell pyroptosis via the ROS/NLRP3 pathway

Abstract

Hyperuricemia closely correlates with the development of atherosclerosis, but little is known of the mechanism by which atherosclerosis progression occurs in hyperuricemia. Atherosclerosis appears to involve pyroptosis, an emerging mechanism of proinflammatory regulated cell death. This study tested the hypothesis that pyroptosis underlies the relationship between hyperuricemia and atherosclerosis, using ApoE−/− mice (a model of atherosclerosis), human umbilical vein endothelial cells (HUVECs), and human atherosclerotic arterial samples. We found that hyperuricemia can aggravate the aortic atherosclerotic plaque‐load in ApoE−/− mice and promote endothelial cell pyroptosis. Additionally, hyperuricemia can increase the levels of serum inflammatory factors (including IL‐1β and IL‐18). Exposure to lipopolysaccharide plus a high concentration of soluble uric acid (≥12 mg/dL) induced cell pyroptosis in HUVECs, as evidenced by increased expression of pyroptosis‐related proteins and elevated release of lactate dehydrogenase (a marker of tissue damage). Further, MCC950, a selective nucleotide‐binding oligomerization domain (NOD)‐like receptor 3 (NLRP3) inflammasome inhibitor, and N‐acetyl‐ l‐cysteine, an antioxidant, attenuated HUVEC pyroptosis by inhibiting activation of the NLRP3 inflammasome and production of intracellular reactive oxygen species (ROS). Finally, we detected significantly higher expression of pyroptosis‐associated proteins in carotid specimens from patients with hyperuricemia. Collectively, our findings suggest that hyperuricemia can aggravate endothelial cell pyroptosis in aortic atherosclerotic plaques, promoting the development of atherosclerosis. Additionally, a high concentration of soluble uric acid can trigger the activation stage of the NLRP3 inflammasome, mediating endothelial cell pyroptosis, and this process is regulated by the cellular ROS level.

Predictive value of the serum uric acid to high-density lipoprotein cholesterol ratio for culprit plaques in patients with acute coronary syndrome

“…Regarding the possible mechanism, hyperuricemia significantly promotes the development of atherosclerotic plaques, downregulates the protein levels of inflammatory genes involved in signaling pathway, promotes the formation of foam cells, and increases lipid peroxidation in macrophages treated with oxidized LDL [ 18 , 19 ]. A previous study also indicated that UA levels are positively associated with inflammatory cytokines, such as interleukin (IL)-6, IL-1β, C-reactive protein, and tumor necrosis factor, and may subsequently induce metabolic abnormalities [ 20 , 21 ].…”

Hyperuricemia: Current State and Prospects

“…Endothelial dysfunction, oxidative stress, inflammation, and activation of the renin-angiotensin-aldosterone system have been proposed as potential mechanisms underlying the cardiovascular effects of HU [15]. HU can exacerbate endothelial cell pyroptosis within aortic atherosclerotic plaques, advancing the progression of atherosclerosis [16]. Furthermore, elevated levels of soluble UA can initiate the activation of the NLRP3 inflammasome [17], leading to endothelial cell pyroptosis, a process modulated by cellular ROS levels.…”

Inflammasomes in Atherosclerosis—From Pathophysiology to Treatment

“…Moreover, in an angiotensin-II-induced hypertension mouse model, the NLRP3 -/- group had reduced blood pressure and largely recovered endothelial function and oxidative stress markers [ 26 ]. Additionally, hyperuricemia, a known risk factor of atherosclerotic cardiovascular disease, may promote atheroprone actions through the NLRP3 inflammasome-mediated endothelial cell pyroptosis [ 27 ].…”