Soluble Uric Acid Promotes Atherosclerosis via AMPK (AMP-Activated Protein Kinase)-Mediated Inflammation

Abstract

Objective: Uric acid is supposed but not yet determined to be associated with atherosclerosis. Uric acid is released from damaged cells to form urate crystal, which is recognized by the immune system to produce IL (interleukin)-1. Danger signals and IL-1 have been shown to play an important role in atherosclerosis. We determined whether the physiological level of soluble uric acid promotes inflammation and develops atherosclerosis. Approach and Results: The secretion of IL-1β from human peripheral blood mononuclear cells mediated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome was promoted by physiological levels in serum uric acid. This augmentation of inflammation was mediated by the regulation of the AMPK (AMP-activated protein kinase)-mTOR (mammalian target of rapamycin) mitochondrial reactive oxygen species and HIF-1α (hypoxia-inducible factor-1α) pathway. In both of uricase transgenic and xanthine oxidase inhibitor–treated mice, decreased levels of uric acid resulted in the activation of AMPK and attenuation of the development of atherosclerotic plaques. Further, acute uric acid reduction by the administration of benzbromarone in healthy humans for 2 weeks significantly decreased plasma IL-18—an inflammasome-dependent cytokine. Conclusions: The data indicate that the development of atherosclerosis and inflammation is promoted by uric acid in vivo. Moreover, the lowering of uric acid levels attenuated inflammation via the activation of the AMPK pathway. This study provides mechanistic evidence of uric acid–lowering therapies for atherosclerosis.

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

“…The molecular mechanism of UAinduced NLRP3/IL-1 b activation is through NF-kB activation and mitochondrial ROS (mROS) ( Figure 2). Consistent with the latest research published by Kimura et al, UA promotes the secretion of IL-1b mediated by NLRP3 inflammasomes via regulating the AMP-activated protein kinase (AMPK)mammalian target of rapamycin (mTOR) mROS and hypoxiainducible factor-1a (HIF-1a) pathway in human peripheral blood mononuclear cells ( Figure 2) (Kimura et al, 2020). In mice treated with uricase gene transfer and XO inhibitor, however, the decrease of UA level promoted the activation of AMPK, and the formation of atherosclerotic plaque was inhibited (Kimura et al, 2020).…”

“…Optical coherence tomography showed a significant increase in plaque rupture in patients with sUA > 8.0 mg/dl (Kobayashi et al, 2018). Recently, Kimura et al demonstrated that UA promotes the secretion of IL-1b mediated by NLRP3 inflammasomes via regulating the AMPK-mTOR mROS and HIF-1a pathway in human peripheral blood mononuclear cells (Kimura et al, 2020). In mice treated with uricase gene transfer and XO inhibitor, however, the decrease of UA level promoted the activation of AMPK and inhibited the formation of atherosclerotic plaque (Kimura et al, 2020).…”

“…Recently, Kimura et al demonstrated that UA promotes the secretion of IL-1b mediated by NLRP3 inflammasomes via regulating the AMPK-mTOR mROS and HIF-1a pathway in human peripheral blood mononuclear cells (Kimura et al, 2020). In mice treated with uricase gene transfer and XO inhibitor, however, the decrease of UA level promoted the activation of AMPK and inhibited the formation of atherosclerotic plaque (Kimura et al, 2020). In addition, the coronary artery calcium (CAC) score can reflect total atherosclerotic burden, which is another effective index to predict future CVD events.…”

Implication of dietary phenolic acids on inflammation in cardiovascular disease

“…Hence, it is safe to mention that suppressing inflammation does not necessarily exert protective effects but may also result in maladaptive consequences. Several lines of evidence have demonstrated the extensive involvement of inflammation in both acute and chronic cardiovascular manifestations such as atherosclerosis (Jiang et al, 2020;Kimura et al, 2020), myocardial infarction (Cremer et al, 2020;Tian et al, 2020), hypertension (Jan-on et al, 2020;Park et al, 2020) and heart failure (Molitor et al, 2020;Pop et al, 2020).…”

Evaluation on prognostic ability of serum uric acid for very old acute coronary syndrome patients with diabetes mellitus

“…Previous research indicated that the hyperuricemic state in the body mainly promotes the development of CHD via the following aspects: 1) Activates platelets, promotes thrombosis, and activates inflammatory mediators to reduce plaque stability [37][38][39] ; 2) Stimulates NADPH oxidase, leading to the abnormal structure and function of vascular endotheliocytes and affects the production of ATP, resulting in the dysfunction of vascular endotheliocytes [40][41][42][43] ; 3) leads to the precipitation of urate crystals and excessive generation of oxygen free radicals, reduces the stability of plaques [44][45][46] . Yuichi Saito [47] et al pointed out that elevated uric acid level was closely related to vascular endothelial dysfunction in ACS patients, which may further cause poor prognosis.…”