Soluble receptor for advanced glycation end products and the risk for incident heart failure: The Atherosclerosis Risk in Communities Study

doi:10.1016/j.ahj.2015.08.008

American Heart Journal

Volume 170, Issue 5, November 2015, Pages 961-967

https://doi.org/10.1016/j.ahj.2015.08.008 Get rights and content

Abstract

Background

Experimental studies in animals suggest that circulating soluble receptor for advanced glycation end products (sRAGE) decrease oxidative stress, inflammation, and fibrosis. The association between sRAGE and incident heart failure has not been systematically examined in a prospective study.

Methods

We conducted a prospective analysis of a subsample of 1,086 participants from the Atherosclerosis Risk in Communities Study who attended visit 2 (1990-1992) without a history of coronary heart disease, stroke, or heart failure and with measured plasma sRAGE levels. Incident heart failure was defined as death from heart failure or hospitalization due to heart failure during a median of 20 years of follow-up.

Results

In this sample of a community-based population (mean age 63 years, 60% women, 78% white), there were 126 incident cases of heart failure. Lower levels of sRAGE were significantly associated with an increased risk of heart failure; the adjusted hazard ratios (95% CIs) of heart failure were 1.0 (reference), 1.81 (0.94-3.49), 1.57 (0.80-3.08), and 3.37 (1.75-6.50), for fourth, third, second, and first quartiles, respectively (P for trend = .001). We did not observe significant interactions by diabetes status or by race or obesity status.

Conclusions

Lower circulating levels of sRAGE are independently associated with the development of heart failure in a community-based population. Our results add to the growing evidence that sRAGE is a valuable predictor of cardiovascular disease.

Section snippets

Study population

The Atherosclerosis Risk in Communities (ARIC) Study is an ongoing cohort study of 15,792 initially middle-aged adults recruited from 4 US communities: Forsyth Country, North Carolina; Jackson, Mississippi; suburban Minneapolis, Minnesota; and Washington County, Maryland.¹⁰ The first examination of participants took place from 1987 to 1989, with 3 follow-up visits, occurring approximately 3 years apart, and a fifth visit in 2011 to 2013. The study population for the present study is composed of

Sources of funding

The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). This research was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant R01-DK076770 and a grant from the American Heart Association to Dr Selvin.

The authors

Results

Baseline characteristics of the study population by overall and race-specific quartiles of sRAGE are shown in Table I. Blacks had substantially lower levels of sRAGE and a higher prevalence of diabetes and hypertension. Regardless of the race/ethnicity, the following were factors associated with low levels of sRAGE: male sex, diabetes, and hypertension; higher BMI; higher CRP; and higher GGT levels.

During a median follow-up of 20 years, there were 126 cases of heart failure among the 1,086

Discussion

In this community-based population of middle-aged individuals without clinically evident cardiovascular disease and normal kidney function, we found that low levels of sRAGE were independently associated with increased risk of heart failure over a median of 20 years of follow-up. Furthermore, addition of sRAGE to the ARIC heart failure prediction model resulted in a small but significant improvement in prediction. As it has been postulated, low sRAGE levels were significantly correlated with

Author contributions

M.L. conceived the study question, analyzed and interpreted the data, and drafted the manuscript and is the guarantor of this work; L.S. analyzed the data; M.K.H., N.M., C.R., A.R., T.B., R.H., C.B., and B.A. interpreted the data and critically revised the manuscript for intellectual content; E.S. conceived the study question, interpreted the data, critically revised the manuscript for intellectual content, obtained funding, and supervised the study.

The following are the supplementary data

Acknowledgements

The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). This research was supported by The National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant R01-DK076770 and a grant from the American Heart Association to Dr Selvin.

The authors

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Advanced glycation end products (AGEs), by-products of glucose metabolism, have been linked to the emergence of cardiovascular disorders (CVD). AGEs can cause tissue damage in four different ways: (1) by altering protein function, (2) by crosslinking proteins, which makes tissue stiffer, (3) by causing the generation of free radicals, and (4) by activating an inflammatory response after binding particular AGE receptors, such as the receptor for advanced glycation end products (RAGE). It is suggested that the soluble form of RAGE (sRAGE) blocks ligand-mediated pro-inflammatory and oxidant activities by serving as a decoy. Therefore, several studies have investigated the possible anti-inflammatory and anti-oxidant characteristics of sRAGE, which may help lower the risk of CVD. According to the results of various studies, the relationship between circulating sRAGE, cRAGE, and esRAGE and CVD is inconsistent. To establish the potential function of sRAGE as a therapeutic target in the treatment of cardiovascular illnesses, additional studies are required to better understand the relationship between sRAGE and CVD. In this review, we explored the potential function of sRAGE in different CVD, highlighting unanswered concerns and outlining the possibilities for further investigation.
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Diabetic cardiomyopathy (DCM), a condition in which myocardial dysfunction is caused by diabetes mellitus, has become an epidemic disorder in the world. DCM initially presents as diastolic relaxation dysfunction and will progress to heart failure in the absence of coronary artery disease, valvular disease, and other conventional cardiovascular risk factors such as hypertension and dyslipidemia. However, the underlying molecular mechanisms of DCM are poorly understood. Recent studies reveal that exosomal miRNAs are associated with multiple DCM risk factors and may act as potential therapeutic targets. Therefore, this review summarizes the recent advancements to understand the role of exosomal miRNAs in DCM development and explores potential preventative and therapeutic strategies.
Multitarget mechanism of Yiqi Jiedu Huayu decoction on diabetic cardiomyopathy based on network pharmacology
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AGEs can promote cross-linking between collagens. Cross-linked collagen is difficult to degrade, leading to myocardial fibrosis and stiffness [33,34]. In addition, accumulated AGEs can activate the NF-κB signaling pathway through RAGE [35].
Yiqi Jiedu Huayu decoction (YJHD) is a traditional Chinese medicine preparation consisting of seven herbs, which has been widely used in the treatment of diabetic cardiomyopathy (DCM) and has achieved positive treatment effects. However, due to its multicomponent, multitarget characteristics, the pharmacological mechanism of YJHD in the treatment of DCM remains unclear.
The potential mechanism of YJHD in the treatment of DCM was explored and validated using network pharmacology, molecular docking technology, and animal experiments. Compounds and targets of YJHD were obtained by the TCMSP, ETCM, and SymMap databases. Next, the targets of DCM were predicted by GeneCards and DisGeNET databases. Then, through a series of screens, the major targets of YJHD for the treatment of DCM were identified. Through GO and KEGG enrichment analysis and signaling pathway mapping, the role of major targets in the treatment of DCM was analyzed. Finally, the results were validated by molecular docking and animal experiments.
95 active ingredients and 38 major targets were identified. Enrichment analysis indicated that YJHD may directly or indirectly regulate multiple pathways, improving myocardial glucose metabolism, inflammation, and fibrosis. The binding of active ingredients to key targets was simulated by molecular docking. In addition, animal models of DCM were established and treated with YJHD, which showed that YJHD can effectively improve the pathological changes of DCM. Furthermore, the regulatory effect of YJHD on certain key pathways were confirmed by western blotting.
Through multicomponent and multitarget analysis, this study reveals the potential mechanisms of YJHD in DCM treatment.
Association between the soluble receptor for advanced glycation end products (sRAGE) and NAFLD in participants in the Atherosclerosis Risk in Communities Study
2021, Digestive and Liver Disease
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Analyses of RAGE activity in cardiovascular disease, diabetes and obesity have suggested that sRAGE may function as a decoy receptor for AGEs thereby preventing RAGE-mediated inflammatory signaling and downstream effects including thrombosis, atherosclerosis and insulin resistance [8,23,31,32]. It has, therefore, been postulated that high levels of sRAGE may serve in a protective role in these disorders whereas low levels may indicate injury and a proinflammatory state [23,31]. Further studies in diabetes, however, have challenged this paradigm for chronic disease and have suggested that constitutive pathway activation may lead to high, rather than low, levels of sRAGE [13,31,33].
Inflammation is key in the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) – a common progressive liver disease. The soluble receptor for advanced glycation end products (sRAGE) attenuates inflammatory signaling; low levels of sRAGE are correlated with increased inflammation.
We sought to describe associations between sRAGE and NAFLD.
We conducted a cross-sectional analysis of 1088 Atherosclerosis Risk in Communities (ARIC) Study participants and used logistic regression to investigate the associations between sRAGE and NAFLD defined by elevated liver enzymes and fibrosis score.
In this community-based sample (n = 1,088, mean age 56 years, 61% female, 78% Caucasian), persons in the lowest vs. highest quartile of sRAGE had significantly higher odds of elevated ALT (OR 2.82, 95% CI 1.18-6.76) but not elevated AST (OR 1.16, 95% CI 0.45-2.99); persons in the lowest vs. highest quartile had significantly lower odds of elevated FIB-4 index (OR 0.56, 95% CI 0.37-0.84).
We found an inverse cross-sectional association between sRAGE and liver inflammation; this is consistent with prior studies linking low sRAGE to inflammatory states. However, we observed a direct association between sRAGE and fibrosis. Our findings suggest that sRAGE is dynamic in NAFLD and patterns may vary with different stages of disease.
The use of the soluble receptor for advanced glycation-end products (sRAGE) as a potential biomarker of disease risk and adverse outcomes
2021, Redox Biology
Citation Excerpt :
For adults who in the main had no documented pre-existing chronic conditions at baseline, findings were mixed. In non-prescreened adults from the general population, positive [80] or no significant associations [40,81] were generally reported, whereas for individuals with no prior history of CVD, the associations with incident disease or adverse events were found to be negative [38,82,83]. In contrast, studies carried out in diabetics (type I or type 2) consistently reported that high levels of sRAGE were predictive of cardiovascular events and/or mortality [26,36,84–86].
The soluble receptor for advanced glycation end-products (sRAGE) has been classically considered a sink for pro-inflammatory RAGE ligands and as such has been associated with protection from inflammatory stress and disease. An alternative, though not mutually exclusive view is that high levels of sRAGE in circulation reflect the overstimulation of cell surface RAGE which if persistent, lead to the amplification of pro-inflammatory processes and the exacerbation of pathological states. With these two scenarios in mind this review focuses on the potential role of sRAGE as a prospective biomarker of disease risk and adverse outcomes.
The different roles for the advanced glycation end products axis in heart failure and acute coronary syndrome settings
2019, Nutrition, Metabolism and Cardiovascular Diseases
Citation Excerpt :
These levels allow sRAGE to function as a decoy for AGEs, limiting their interaction with RAGE and conferring vascular protection [32]. Supporting this, in a cohort from the ARIC study without a history of coronary artery disease, stroke or HF, lower circulating levels of sRAGE were independently associated with the development of HF over a median of 20 years of follow-up [33]. However, under several pathological conditions, such as hypertension [29], hypercholesterolemia [34], inflammation [35] or coronary artery disease [28,31], levels of sRAGE become reduced, limiting its ability to work as a decoy.
This work aimed to compare the behavior of the advanced glycation end products (AGEs) and their soluble receptor (sRAGE) in two cohorts of patients: those with heart failure (HF) and acute coronary syndrome (ACS).
A unicentric observational clinical study was performed in 102 patients with ACS and 102 patients with chronic HF matched by age and gender. At inclusion, fluorescent AGEs were measured by quantitative fluorescence spectroscopy of plasma, and total sRAGE and endogenous secretory RAGE (esRAGE) levels were determined by enzyme-linked immunosorbent assay kits. A 5-year follow-up period was established for recording cardiac death (primary endpoint) and the incidence of non-fatal myocardial infarction or HF readmission (secondary endpoints). Higher glycation parameters were observed in HF patients, whereas no differences in sRAGE forms were found between HF and ACS cohorts, except for cRAGE, which was higher in HF. Associations between glycation parameters and sRAGE forms were observed in HF, but not in ACS. Differences were also evidenced in the long-term prognosis of each cohort: esRAGE showed an independent prognostic value for cardiac death or non-fatal cardiovascular events in HF, but none of the AGE–RAGE variables were predictors in ACS.
A different role for the AGE–RAGE axis was observed in HF and ACS. All the sRAGE forms were directly related with glycation parameters in HF, but not in ACS. The independent value of the sRAGE forms on each cardiovascular disease was supported by esRAGE being an independent predictor of bad long-term prognosis only for HF.

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Clinical InvestigationSoluble receptor for advanced glycation end products and the risk for incident heart failure: The Atherosclerosis Risk in Communities Study

Abstract

Background

Methods

Results

Conclusions

Section snippets

Study population

Sources of funding

Results

Discussion

Author contributions

Acknowledgements

Metabolism

Trends Endocrinol Metab

Atherosclerosis

Clin Biochem

J Card Fail

Am J Cardiol

Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases

J Clin Endocrinol Metab

Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications

Nat Clin Pract Endocrinol Metab

The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses

J Clin Invest

Comment on: Selvin et al. sRAGE and risk of diabetes, cardiovascular disease, and death. Diabetes 2013;62:2116-2121

Diabetes

The biology of RAGE and its ligands: uncovering mechanisms at the heart of diabetes and its complications

Curr Diab Rep

Biomarkers in heart failure

N Engl J Med

The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators

Am J Epidemiol

sRAGE and risk of diabetes, cardiovascular disease, and death

Diabetes

Clinical Investigation
Soluble receptor for advanced glycation end products and the risk for incident heart failure: The Atherosclerosis Risk in Communities Study