Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia

Abstract

Macrophages in the atheroma region produce matrix metalloproteinases (MMPs) and decrease plaque stability. Tissue oxygen tension decreases in the arterial wall of the atherosclerotic region. Hypoxia inducible factor (HIF)-1α plays a critical role in the transcriptional activation of hypoxia inducible genes. However, the precise roles of HIF-1α independent pathways in hypoxic responses are largely unknown. Xanthine oxidase (XO) is an enzyme that utilizes molecular oxygen and produces reactive oxygen species (ROS). Here, we show that ROS derived from XO increases MMP-3, -10, and -13 expression in murine macrophages. We found that the transcript levels of macrophage MMP-3, -10, and -13 were increased in hypoxic conditions. Hypoxia induced MMP expression in HIF-1α deficient macrophages. N-acetylcysteine (NAC) or febuxostat, an XO inhibitor, suppressed MMP expression in murine macrophages. Febuxostat decreased the incidence of plaque rupture in apolipoprotein-E-deficient mice. Our results indicate that febuxostat stabilized atherosclerotic plaque via suppressing the activities of macrophage MMP-9 and -13. Febuxostat administration is a potential therapeutic option in the management of atherosclerotic patients.

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

“…42 The local oxygen tension may accelerate atherosclerotic plaque vulnerability and rupture by activating MMPs via XO. 43 While hypoxic environment could affect XO activity and ROS production, the role of XO in macrophage function is not yet fully elucidated and a potential inflammatory microenvironment that shifts macrophages into M1 phenotype expressing XO may be only speculated.…”

Effect of febuxostat on the level of malondialdehyde‐modified low‐density lipoprotein, an oxidative stress marker: A subanalysis of the PRIZE study

“…[6][7][8] Febuxostat selectively suppresses xanthine oxidase (XO), the enzyme responsible for the conversion of hypoxanthine to xanthine and then to uric acid (UA), thereby reducing the UA levels. Hence, this drug has an antioxidant effect, 6,[9][10][11][12][13][14][15][16][17][18][19][20] which was shown to be robust in various basic and animal studies. [9][10][11]13,15,[17][18][19] Many clinical studies have also demonstrated the antioxidant effects of febuxostat 6,12,14,16,20,21 ; however, the results are inconsistent.…”

“…Hence, this drug has an antioxidant effect, 6 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 which was shown to be robust in various basic and animal studies. 9 , 10 , 11 , 13 , 15 , 17 , 18 , 19 Many clinical studies have also demonstrated the antioxidant effects of febuxostat 6 , 12 , 14 , 16 , 20 , 21 ; however, the results are inconsistent. Sezai et al stated that, in hyperuricemic patients with cardiovascular disease treated with a combination of febuxostat and topiroxostat, the oxidized LDL level was significantly lower in the febuxostat group at 3 months, but the difference disappeared at 6 months.…”

Special Issue: Hypoxia-Inducible Factors: Regulation and Therapeutic Potential

“…In this Special Issue, we invited research and review papers in various areas of oxygen biology research that focused on the fundamental understanding of HIF signaling pathways and related gene expression profiling, as well as pharmacogenomic biomarkers, molecular targets driving the regulation of human physiology and pathophysiology, and validation in animal models. As a result, we published six original papers and three review articles in this Special Issue [ 1 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

“…Additionally, induction was found to be inhibited by febuxostat, a xanthine oxidase inhibitor. Febuxostat administration is a potential therapeutic option for disease management in atherosclerotic patients [ 20 ].…”