Review Article
Role of advanced glycation end products in hypertension and cardiovascular risk: human studies

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Abstract

Reactive derivatives of nonenzymatic glucose-protein condensation reactions, as well as lipids and nucleic acids exposed to reducing sugars, form a heterogeneous group of irreversible adducts called “advanced glycation endproducts” (AGEs). Numerous studies have investigated the role of the AGEs in diabetic subjects; however, the role on hypertension and the cardiovascular system has been less intensively investigated in clinical studies. This review summarizes clinical data on AGEs and its action on the receptor of AGEs (RAGE) with respect to blood pressure and vascular disease to update the clinician on this important pathway. In summary, clinical data on the AGE-RAGE axis at the moment does not provide evidence for a role in hypertension but for vascular disease, including macrocirculation as well as microcirculation. Potential causes, such as local deposition or signaling pathways are discussed in context with the literature. Finally, the small number of interventional studies is summarized, pointing to a need for more interventional trials with respect to AGEs and vascular disease. Animal data are explicitly excluded to strengthen the clinical focus and to increase the relevance for clinicians.

Introduction

Reactive derivatives of nonenzymatic glucose–protein condensation reactions, as well as lipids and nucleic acids exposed to reducing sugars, form a heterogeneous group of irreversible adducts called “advanced glycation endproducts” (AGEs). AGEs were originally characterized by their yellow-brown fluorescent color and their ability to form crosslinks to and between amino groups. The term AGEs is now used for a broad range of advanced products of the Maillard reaction that neither show color and fluorescence, nor occur as crosslinks in proteins.1

The formation of AGEs in vitro and in vivo depends on the turnover rate of the chemically modified target, time, and sugar concentration. Therefore, it is not surprising that accumulation of AGEs was first noticed in humans during aging and at an accelerated rate during the course of diabetes.2, 3 In both circumstances, cardiovascular risk is augmented, and vascular disease is more frequent.

Schleicher et al2 presented the accumulation of N-epsilon-(carboxymethyl)lysine (CML) in the dermis and the nucleus pulposus of intervertebral discs during aging. Moreover, they were able to demonstrate that dermal CML deposition was predominantly present in dermal arteries. Based on this observation, predominantly CML and N-epsilon-(carboxyethyl)lysine (CEL) were investigated in the following studies, and it was suggested that local deposition of AGEs may influence vascular function and blood pressure homeostasis.

AGEs act on a receptor called receptor of AGE (RAGE). This receptor is situated in vascular tissue. Moreover, RAGE modulates several pathways known to influence vascular function and blood pressure homeostasis.4 These mechanisms include endothelial nitric oxide synthase (eNOS),5 NADPHox,3 and MAP/ERK kinases.6 Therefore, AGEs are not only markers, but potentially mediators of chronic vascular complications.

The AGE-RAGE-axis is complicated by 2 additional factors. First, RAGE is also present in the bloodstream as a soluble form (sRAGE). sRAGE reflects either proteolytically cleaved c-truncated RAGE originally based at the cell membrane or intracellular RAGE, which is located in endosomes and is externalized by exocytosis.7

The role of sRAGE is still a matter of discussion and is raised in this review as well. Several authors describe sRAGE as a protective molecule neutralizing systemic AGEs; however, newer prospective data are rather conflicting. Second, RAGE is not only a receptor for AGEs, but 2 additional groups of proteins act on RAGE: S100 proteins and high-mobility group box-1 (HMGB-1).

During the transmigration process in macrophages, S100 protein dimers are formed and consecutively excreted. These S100 protein dimers bind to RAGE and induce proinflammatory action. The clinical relevance of these S100 protein dimers has been demonstrated in patients with acute coronary syndrome.8

The other protein binding to RAGE is HMGB-1, which is localized in the nucleus and is externalized only if cell damage has taken place. A clinical association between RAGE and HMGB-1 has been demonstrated for community-acquired pneumonia9 and in patients with asthma.10

This review summarizes clinical data on the AGE-RAGE axis with respect to blood pressure and vascular disease to update the clinician on this important pathway (Table 1). Animal data are explicitly excluded to strengthen the clinical focus and to increase the relevance for clinicians.

Section snippets

Blood Pressure

Schram et al11 performed a cross-sectional nested case-control study in 543 European individuals who were diagnosed with type 1 diabetes when younger than 36 years. In this study, no association between AGEs and mean arterial pressure was observed; however, CML and CEL were directly associated with systolic pressure and inversely with diastolic pressure. Pulse pressure was strongly and independently associated with AGEs, CML, and CEL in young type 1 diabetic individuals. As elevated pulse

Prospective Studies

Hartog et al35 included 102 patients with chronic heart failure with an average left ventricular ejection fraction of 28% ± 9%. The follow-up period was 1.7 (1.2–1.9) years. Most patients were New York Heart Association (NYHA) functional class II and III.

Cross-sectional trend analysis revealed that CML levels significantly increased NYHA functional class. Survival analysis for the combined end point of death, heart transplantation, ischemic cardiovascular event, and hospitalization for heart

Interventional Trials

As demonstrated, the AGE-RAGE axis is involved in cardiovascular risk. Therefore, 2 questions arise: (1) Do substances exist that directly interfere with the AGE-RAGE axis? (2) In how far do established cardiovascular acting pharmacological substances interfere with the AGE-RAGE axis?

Interventional trials on the field of AGE-RAGE are scarce, although in animal experiments, several substances have been demonstrated to reduce AGE accumulation and to influence the signaling pathway. However, no

Summary

Numerous studies have investigated the role of the AGE-RAGE axis in diabetic subjects; however, the role of hypertension and the cardiovascular system has been less intensively investigated in clinical studies. No evidence exists that the AGE-RAGE axis has a major influence on essential hypertension. By contrast, in preeclampsia, an association with appearance and severity has been observed. Although the pathomechanism remains uncertain, the inflammatory aspect of this disease can be associated

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