Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression

Abstract

Background and Purpose: XO (xanthine oxidase) is a key enzyme of uric acid metabolism and is thought to contribute to oxidative pathways that promote atherosclerotic plaque progression, yet its role in plaque destabilization is not well elucidated. We hypothesized that XO is expressed in carotid plaque from symptomatic patients in association with cardiovascular risk factors. Methods: Patients were stratified by symptoms, defined as presentation with an ipsilateral cerebral ischemic event. Carotid atherosclerotic plaques were obtained from 44 patients with symptomatic plaque and 44 patients without ischemic cerebral events. Protein expression of XO was evaluated by immunohistochemical staining and the percentage of cells expressing XO and CD68 (macrophage marker) compared between the groups. Biochemical and demographic cardiometabolic risk factors of study participants also were measured. Results: Carotid atherosclerotic plaques from symptomatic patients were associated with significantly higher XO expression versus asymptomatic plaque (median [interquartile range]: 1.24 [2.09] versus 0.16 [0.34]; P <0.001) and with significantly higher circulating uric acid levels (mean±SD: 7.36±2.10 versus 5.37±1.79 mg/dL; P <0.001, respectively). In addition, XO expression in atherosclerotic carotid plaque was inversely associated with serum high-density lipoproteins cholesterol levels ( P =0.010, r =−0.30) and directly with circulating uric acid levels ( P <0.001, r =0.45). The average percentage of macrophages that expressed XO was significantly higher in symptomatic versus asymptomatic plaques (median [interquartile range]: 93.37% [25] versus 46.15% [21], respectively; P <0.001). Conclusions: XO overexpression in macrophages is associated with increased serum uric acid and low high-density lipoproteins cholesterol levels and may potentially have a mechanistic role in carotid plaque destabilization. The current study supports a potential role for uric acid synthesis pathway as a target for management of carotid atherosclerosis in humans.

Uric Acid Expression in Carotid Atherosclerotic Plaque and Serum Uric Acid Are Associated With Cerebrovascular Events

“…We have previously reported that the expression of XO, a key enzyme of UA metabolism, correlates with vulnerability of carotid plaques. 6 To extend the implications of our previous study, we hypothesized and demonstrated that UA, the final product of XO, accumulates in carotid atherosclerotic plaques quantitatively more in symptomatic than asymptomatic patients. Consistently with our findings, a single study has investigated the UA presence in atherosclerotic rather than nonatherosclerotic carotid arteries.…”

“…In a previous study, we have found a higher XO expression in carotid atherosclerotic plaques from symptomatic versus asymptomatic patients. 6 In the current study, we expanded the research from the sole expression of XO to the detection of UA in carotid plaque tissue. To our knowledge, the presence of UA in atherosclerotic plaques associated with cerebrovascular events has not been reported.…”

Enlarged Pericarotid Lymph Nodes Suggest Recent Ischemic Symptoms in Patients with Carotid Atherosclerosis

“…Symptomatic patients had a history of amaurosis fugax, transient ischemic attack, or ischemic stroke ipsilateral to the extracted plaques within six months before the endarterectomy procedure. Conversely, asymptomatic patients did not have a history of cerebrovascular events ( 17 ). Data on venous blood samples, and the clinical and demographic characteristics of the participants were gathered from patients before CEA.…”

Xanthine oxidoreductase: A leading actor in cardiovascular disease drama

“…Furthermore, the overexpression of XOR in macrophages was associated with a low level of HDL, concurring to the formation of cholesterol crystals in the atheroma and the macrophage inflammatory response. ROS derived from XOR contributed to the oxidation of macromolecules and the activation of cell death signals that can lead to cerebrovascular events [ 36 ].…”