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Uric acid and essential hypertension: the endothelial connection

Schmitz, Boris; Brand, Stefan-Martin

doi: 10.1097/HJH.0000000000001109
EDITORIAL COMMENTARIES

Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany

Correspondence to Stefan-Martin Brand, MD, PhD, University Hospital Muenster, Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, Horstmarer Landweg 39, D-48149 Muenster, Germany. Tel: +49 251 83 52996; fax: +49 251 83 35387; e-mail: stefan-martin.brand@ukmuenster.de

Elevated uric acid concentrations are commonly observed in patients with hypertension and chronic kidney disease [1,2], coronary artery disease [3], chronic heart failure [4], acute myocardial infarction and stroke [5]. Of note, hyperuricemia has been associated with an increased risk for incident hypertension independent of traditional hypertension risk factors [2]. Strong evidence for a causal relationship between elevated uric acid plasma levels and hypertension has been provided by earlier research of Feig and Johnson [6,7]. In a screening of 125 children (6–18 years), they detected serum uric acid concentrations more than 5.5 mg/dl in 89% of patients with essential hypertension and in 30% of patients with secondary hypertension [6]. Subsequently, they demonstrated that allopurinol (200 mg twice daily for 4 weeks) lowered uric acid levels in adolescents with newly diagnosed hypertension from a mean 7.0 mg/dl to 4.2 mg/dl. Blood pressure during allopurinol treatment was consistently reduced by −6.9 mmHg for SBP and −5.1 mmHg for DBP (vs placebo, −2.0 mmHg SBP/−2.4 mmHg DBP) [7].

Beyond these epidemiologic and interventional observations, we have learnt that uric acid is a biologically active molecule [8,9]. In contrast to the replicated associations of increased uric acid levels with cardiovascular disease, uric acid has been suggested to be one of the major antioxidants in human plasma [10,11]. At physiological concentrations, the uric acid anion urate has the ability to scavenge oxygen radicals and may protect the erythrocyte membrane from lipid oxidation [10]. However, uric acid does not scavenge superoxide, and the uric acid antioxidative activity depends on a hydrophilic environment such as human plasma [10,11]. In addition, it has been postulated that uric acid may turn into a prooxidant risk factor under certain inflammatory conditions such as atheromatous plaque formation [5], a concept known as the prooxidant urate redox shuttle theory [12].

In this issue of the Journal of Hypertension, Scheepers et al. [13] remind us of another important aspect of uric acid and the purine catabolism, pointing to the process of uric acid production, the involved metabolites and their potential association with essential hypertension. Uric acid is an end product of the purine catabolic pathway [14], and uric acid production is reported to be highest in the liver and intestine [15]. Of note, significant uric acid production has been detected in microvascular endothelial cells from several tissues [15–17]. At the enzyme level, the breakdown of adenine-based and guanine-based purine compounds depends on the enzyme xanthine oxidoreductase (XOR), the only enzyme capable of producing uric acid [8]. In this process, reactive oxygen species (ROS) are generated. In this context, Scheepers et al. [13] suggested that the process of uric acid production by XOR (and not hyperuricemia per se) is associated with hypertension as a result of oxidative stress and endothelial dysfunction. They assessed the risk of hypertension in relation to XOR variants proposing that genetic variation at the XOR locus is associated with XOR expression.

XOR is a housekeeping gene [18] coding for two distinct enzymatic forms: xanthine dehydrogenase (XDH, EC1.1.1.204) and xanthine oxidase (EC1.1.3.22). Both enzymes catalyse the oxidation of the intermediate xanthine to uric acid. XDH and xanthine oxidase are homodimers of ∼300 kDa with each subunit containing a single peptide chain that binds one molybdopterin cofactor, two nonidentical 2Fe–2S centres and one flavin adenine dinucleotide (FAD) cofactor [19]. The oxidation of xanthine takes place at the molybdenum centre, and electrons are transferred to the FAD cofactor with nicotinamide adenine dinucleotide (NAD+) and molecular oxygen as competing final electron acceptor. The main differences in the catalytic properties of XDH and xanthine oxidase are that XDH–FAD reacts predominantly with NAD+, whereas xanthine oxidase FAD has higher reactivity towards molecular oxygen producing higher levels of H2O2 [19]. Although XDH is the predominant enzymatic form found in normal tissues with rather low activity [15], the xanthine oxidase form dominates in tissues subjected to injury and ischaemic conditions [20]. Conversion of XDH to xanthine oxidase occurs posttranslationally through the oxidation of sulfhydryl residues or proteolysis. It has also been suggested that complement component 5, TNF-α and N-formyl-methionyl-leucyl-phenylalanine can induce the rapid conversion of XDH to xanthine oxidase in intact endothelial cells [21]. XDH may also be set free into the blood during reperfusion after ischaemia where oxidation and proteolysis to xanthine oxidase can occur [15]. Xanthine oxidase can re-enter into intact cells or be active at the outer surface of the endothelial cell plasma membrane [15]. Allopurinol inhibits the production of uric acid at the molecular level by competition for xanthine at XOR and thus also prevents H2O2 production [22]. Consistently, it has been reported that allopurinol, in addition to its uric-acid-lowering action, has ‘pleiotropic’ effects and may improve endothelial function and endothelium-dependent vasodilation [23].

It is also true that extracellular uric acid can enter endothelial cells and vascular smooth muscle cells through SLC22A12 (URAT1), SLC2A9 (GLUT9) and potentially other transporters [24,25] activating the NF-κB axis leading to an increase in MCP-1, IL-8, VCAM-1 and ICAM-1 [26]. Interestingly, Scheepers et al. [13] did not detect an association of uric acid serum levels with XOR variants. This gives rise to the conjecture that intraendothelial xanthine oxidase activity and increased ROS production might be a factor involved in endothelial dysfunction leading to the development of essential hypertension. As XOR variants have been identified to be associated with individual XOR enzyme activity variation in vitro [27] and a specific method to measure endogenous xanthine oxidase activity in living endothelial cells has recently been developed [17], future studies could provide additional information to confirm this link. As most figures of the interested community would conclude ‘the paper is open for discussion’.

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ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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