Biomarker potential and regulatory mechanisms of sRAGE in cardiovascular diseases

doi:10.3969/j.issn.1006-7795.2025.06.016

Abstract

Abstract: Cardiovascular diseases (CVD) represent a leading cause of morbidity and mortality worldwide, involving complex metabolic pathways and molecular mechanisms. Recent studies have highlighted the role of advanced glycation end products (AGEs), their receptor RAGE, and soluble RAGE (sRAGE) in CVD progression. AGEs activate inflammatory and oxidative stress pathways through RAGE, promoting pathological processes like atherosclerosis, while sRAGE acts as a “decoy” receptor, neutralizing AGEs and mitigating RAGE activation. Evidence suggests that sRAGE levels dynamically change in conditions such as atherosclerosis, coronary artery disease, hypertension, and heart failure, indicating its potential as a biomarker and therapeutic target. Further research is required to elucidate the mechanisms and clinical applications of sRAGE, offering new perspectives for CVD prediction, evaluation, and treatment.

Key words: cardiovascular diseases, soluble receptor for advanced glycation end products, coronary artery disease, heart failure, atherosclerosis, biomarkers

CLC Number:

R541

Shen Xueqian, Jiang Xue, Guo Caixia. Biomarker potential and regulatory mechanisms of sRAGE in cardiovascular diseases[J]. Journal of Capital Medical University, 2025, 46(6): 1082-1092.

References

［1］中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告2022概要［J］. 中国循环杂志, 2023, 38(6): 583-612.
［2］Mensah G A, Fuster V, Murray C J L, et al. Global burden of cardiovascular diseases and risks, 1990-2022［J］. J Am Coll Cardiol, 2023, 82(25): 2350-2473.
［3］Selvin E, Halushka M K, Rawlings A M, et al. sRAGE and risk of diabetes, cardiovascular disease, and death［J］. Diabetes, 2013, 62(6): 2116-2121.
［4］Erusalimsky J D. The use of the soluble receptor for advanced glycation-end products (sRAGE) as a potential biomarker of disease risk and adverse outcomes［J］. Redox Biol, 2021, 42: 101958.
［5］Shen C Y, Lu C H, Wu C H, et al. The development of Maillard reaction, and advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling inhibitors as novel therapeutic strategies for patients with AGE-related diseases［J］. Molecules, 2020, 25(23): 5591.
［6］Daffu G, Del Pozo C H, O'Shea K M, et al. Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond［J］. Int J Mol Sci, 2013, 14(10): 19891-19910.
［7］Fukami K, Yamagishi S I, Okuda S. Role of AGEs-RAGE system in cardiovascular disease［J］. Curr Pharm Des, 2014, 20(14): 2395-2402.
［8］Basta G. Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications［J］. Atherosclerosis, 2008, 196(1): 9-21.
［9］Lindsey J B, Cipollone F, Abdullah S M, et al. Receptor for advanced glycation end-products (RAGE) and soluble RAGE (sRAGE): cardiovascular implications［J］. Diab Vasc Dis Res, 2009, 6(1): 7-14.
［10］Sharifi-Zahabi E, Sharafabad F H, Abdollahzad H, et al. Circulating advanced glycation end products and their soluble receptors in relation to all-cause and cardiovascular mortality: a systematic review and meta-analysis of prospective observational studies［J］. Adv Nutr, 2021, 12(6): 2157-2171.
［11］Delrue C, Delanghe J R, Speeckaert M M. The role of sRAGE in cardiovascular diseases［J］. Adv Clin Chem, 2023, 117: 53-102.
［12］Ramasamy R, Yan S F, Schmidt A M. RAGE: therapeutic target and biomarker of the inflammatory response-the evidence mounts［J］. J Leukoc Biol, 2009, 86(3): 505-512.
［13］Santilli F, Vazzana N, Bucciarelli L G, et al. Soluble forms of RAGE in human diseases: clinical and therapeutical implications［J］. Curr Med Chem, 2009, 16(8): 940-952.
［14］Raucci A, Cugusi S, Antonelli A, et al. A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (Adam10)［J］. FASEB J, 2008, 22(10): 3716-3727.
［15］Faiz A, Van Den Berge M, Vermeulen C J, et al. AGER expression and alternative splicing in bronchial biopsies of smokers and never smokers［J］. Respir Res, 2019, 20(1): 70.
［16］Sabbatinelli J, Castiglione S, Macrì F, et al. Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study［J］. Cardiovasc Diabetol, 2022, 21(1): 95.
［17］Katakami N. Can soluble receptor for advanced glycation end-product (sRAGE) levels in blood be used as a predictor of cardiovascular diseases?［J］. Atherosclerosis, 2017, 266: 223-225.
［18］Bucciarelli L G, Wendt T, Qu W, et al. RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice［J］. Circulation, 2002, 106(22): 2827-2835.
［19］Ha C H, Kim S, Chung J, et al. Inhibitory effect of soluble RAGE in disturbed flow-induced atherogenesis［J］. Int J Mol Med, 2014, 32(2): 373-380.
［20］Shao M Z, Yu M Y, Zhao J, et al. miR-21-3p regulates AGE/RAGE signalling and improves diabetic atherosclerosis［J］. Cell Biochem Funct, 2020, 38(7): 965-975.
［21］Shu M, Cheng W Z, Jia X, et al. AGEs promote atherosclerosis by increasing LDL transcytosis across endothelial cells via RAGE/NF-κB/caveolin-1 pathway［J］. Mol Med, 2023, 29(1): 113.
［22］Wasim R, Mahmood T, Siddiqui M H, et al. Aftermath of AGE-RAGE cascade in the pathophysiology of cardiovascular ailments［J］. Life Sci, 2022, 307: 120860.
［23］Tae H J, Kim J M, Park S, et al. The N-glycoform of sRAGE is the key determinant for its therapeutic efficacy to attenuate injury-elicited arterial inflammation and neointimal growth［J］. J Mol Med, 2013, 91(12): 1369-1381.
［24］Liu Y, Yu M L, Zhang L, Cao Q, et al. Soluble receptor for advanced glycation end products mitigates vascular dysfunction in spontaneously hypertensive rats［J］. Mol Cell Biochem, 2016, 419(1/2): 165-176.
［25］Gelžinsk J, Mayer O, Jr, Seidlerová J, et al. Soluble receptor for advanced glycation end-products independently influences individual age-dependent increase of arterial stiffness［J］. N Hypertens Res, 2014, 43(2): 111-120.
［26］Grauen Larsen H, Marinkovic G, Nilsson P M, et al. High plasma sRAGE (soluble receptor for advanced glycation end products) is associated with slower carotid intima-media thickness progression and lower risk for first-time coronary events and mortality［J］. Arterioscler Thromb Vasc Biol, 2019, 39(5): 925-933.
［27］李冬云. 妊娠期高血压产妇N端脑钠肽前体、可溶性晚期糖基化终末产物受体的变化及其与心功能的关系［J］. 实用临床医药杂志, 2020, 24 (9): 61-65.
［28］Nakamura K, Yamagishi S I, Adachi H, et al. Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease［J］. Diabetes Metab Res Rev, 2007, 23(5): 368-371.
［29］Ghosh S, Kapoor D, Vijayvergiya R, et al. Correlation between soluble receptor for advanced glycation end products levels and coronary artery disease in postmenopausal nondiabetic women［J］. World J Cardiol, 2021, 13(5): 130-143.
［30］Falcone C, Bozzini S, D'angelo A, et al. Plasma levels of soluble receptor for advanced glycation end products and coronary atherosclerosis: possible correlation with clinical presentation［J］. Dis Markers, 2013, 35(3): 135-140.
［31］Lindsey J B, De Lemos J A, Cipollone F, et al. Association between circulating soluble receptor for advanced glycation end products and atherosclerosis: observations from the Dallas heart study［J］. Diabetes Care, 2009, 32(7): 1218-1220.
［32］Pearce C, Islam N, Bryce R, et al. Advanced glycation end products: receptors for advanced glycation end products axis in coronary stent restenosis: a prospective study［J］. Int J Angiol, 2018, 27(4): 213-222.
［33］Reichert S, Triebert U, Santos A N, et al. Soluble form of receptor for advanced glycation end products and incidence of new cardiovascular events among patients with cardiovascular disease［J］. Atherosclerosis, 2017, 266: 234-239.
［34］Malik A, Mahmood M, Mushtaq M, et al. Precipitation of acute coronary syndrome in an interactive association of oxidative stress biomarkers with soluble receptor for advanced glycation end-products［J］. J Taibah Univ Sci, 2023, 17(1): 2273605.
［35］Qiu H, Li W P, Shen X H, et al. Dynamic fluctuations of advanced glycation end products and its C-terminal truncated receptor level in patients with acute ST-segment elevation myocardial infarction and undergoing diabetes or not［J］. Can J Diabetes, 2021, 87(30): 1-8.
［36］Redondo A, Paradela-Dobarro B, Moscoso I, et al. Correction to: galectin-3 and soluble RAGE as new biomarkers of post-infarction cardiac remodeling［J］. J Mol Med, 2021, 99(7): 955-956.
［37］Cai X Y, Lu L, Wang Y N, et al. Association of increased S100B, S100A6 and S100P in serum levels with acute coronary syndrome and also with the severity of myocardial infarction in cardiac tissue of rat models with ischemia-reperfusion injury［J］. Atherosclerosis, 2011, 217(2): 536-542.
［38］Park H J, Baek J Y, Shin W S, et al. Soluble receptor of advanced glycated endproducts is associated with plaque vulnerability in patients with acute myocardial infarction［J］. Circ J, 2011, 75(7): 1685-1690.
［39］罗晓萌, 江雪, 杜凤和, 等. 急性冠状动脉综合征患者血浆sRAGE、IFN-γ浓度及其与冠状动脉病变严重程度的关系［J］. 首都医科大学学报, 2023, 44(2): 272-279.
［40］Liu Y M, Guo X Y, Zhang J, et al. Protective effects of the soluble receptor for advanced glycation End-Products on pyroptosis during myocardial ischemia-reperfusion［J］. Oxid Med Cell Longev, 2021, 2021: 9570971.
［41］Han X J, Guo X Y, Chang J, et al. Integrinβ3 mediates the protective effects of soluble receptor for advanced glycation end-products during myocardial ischemia/reperfusion through AKT/STAT3 signaling pathway［J］. Apoptosis, 2022, 27(5/6): 354-367.
［42］Zhang J, Han X J, Chang J, et al. Soluble RAGE attenuates myocardial I/R injuries via FoxO3-Bnip3 pathway［J］. Cell Mol Life Sci, 2022, 79(5): 269.
［43］Dang M Q, Zeng X J, Chen B X, et al. Soluble receptor for advance glycation end-products inhibits ischemia/reperfusion-induced myocardial autophagy via the STAT3 pathway［J］. Free Radic Biol Med, 2019, 130: 107-119.
［44］Cao X X, Li B, Han X J, et al. Soluble receptor for advanced glycation end-products promotes angiogenesis through activation of STAT3 in myocardial ischemia/reperfusion injury［J］. Apoptosis, 2020, 25(5/6): 341-353.
［45］Yoon S J, Park S, Park C, et al. Association of soluble receptor for advanced glycation end-product with increasing central aortic stiffness in hypertensive patients［J］. Coron Artery Dis, 2012, 23(2): 85-90.
［46］Šebeková K, Gurecká R, Csongová M, et al. Sex differences in association of elevated blood pressure with variables characterizing cardiometabolic risk in young subjects with or without metabolic abnormalities［J］. Int J Environ Res Public Health, 2020, 17(10): 3612.
［47］Gryszczyńska B, Budzyń M, Begier-Krasińska B, et al. Association between advanced glycation end products, soluble rage receptor, and endothelium dysfunction, evaluated by circulating endothelial cells and endothelial progenitor cells in patients with mild and resistant hypertension［J］. Int J Mol Sci, 2019, 20(16): 3942.
［48］Dimitriadis K, Tsioufis C, Kasiakogias A, et al. Soluble receptor for advanced glycation end-product levels are related to albuminuria and arterial stiffness in essential hypertension［J］. Nutr Metab Cardiovasc Dis, 2013, 23(4): 382-388.
［49］Nakamura K, Yamagishi S, Nakamura Y, et al. Telmisartan inhibits expression of a receptor for advanced glycation end products(RAGE)in angiotensin-II-exposed endothelial cells and decreases serum levels of soluble RAGE in patients with essential hypertension［J］. Microvasc Res, 2005, 70(3): 137-141.
［50］Maresca A M, Guasti L, Bozzini S, et al. sRAGE and early signs of cardiac target organ damage in mild hypertensives［J］. Cardiovasc Diabetol, 2019, 18(1): 17.
［51］Hogan M, Cerami A, Bucala R. Advanced glycosylation endproducts block the antiproliferative effect of nitric oxide. Role in the vascular and renal complications of diabetes mellitus［J］. J Clin Invest, 1992, 90(3): 1110-1115.
［52］Reiser K, McCormick R J, Rucker R B. Enzymatic and nonenzymatic cross-linking of collagen and elastin［J］. FASEB J, 1992, 6(7): 2439-2449.
［53］Lancefield T F, Patel S K, Freeman M, et al. The receptor for advanced glycation end products (RAGE) is associated with persistent atrial fibrillation［J］. PLoS One, 2016, 11(9): e0161715.
［54］Raposeiras-Roubín S, Rodio-Janeiro B K, Grigorian-Shamagian L, et al. Evidence for a role of advanced glycation end products in atrial fibrillation［J］. Int J Cardiol, 2012, 157(3): 397-402.
［55］Yang P S, Kim T H, Uhm J S, et al. High plasma level of soluble RAGE is independently associated with a low recurrence of atrial fibrillation after catheter ablation in diabetic patient［J］. Europace, 2016, 18(11): 1711-1718.
［56］Jia H, Kang L, Lu S Y, et al. Circulating soluble receptor of advanced glycation end product is associated with bicuspid aortic aneurysm progression via NF-κB pathway［J］. Interact Cardiovasc Thorac Surg, 2022, 34(2): 274-282.
［57］Raposeiras Roubin S, Rodino Janeiro B K, Grigorian Shamagian L, et al. Implication of AGE-RAGE axis in atrial fibrillation in patients with heart failure［J］. European Journal of Heart Failure, Supplement, 2011, 10: S223.
［58］Prasad K. AGE-RAGE stress in the pathophysiology of atrial fibrillation and its treatment［J］. Int J Angiol, 2020, 29(2): 72-80.
［59］Liu Y, Yu M L, Zhang Z G, et al. Blockade of receptor for advanced glycation end products protects against systolic overload-induced heart failure after transverse aortic constriction in mice［J］. Eur J Pharmacol, 2016, 791: 535-543.
［60］Lu L, Zhang Q, Xu Y, et al. Intra-coronary administration of soluble receptor for advanced glycation end-products attenuates cardiac remodeling with decreased myocardial transforming growth factor-beta1 expression and fibrosis in minipigs with ischemia-reperfusion injury［J］. Chin Med J, 2010, 123(5): 594-598.
［61］Scavello F, Zeni F, Milano G, et al. Soluble receptor for advanced glycation end-products regulates age-associated cardiac fibrosis［J］. Int J Biol Sci, 2021, 17(10): 2399-2416.
［62］曹贤贤, 韩雪洁, 王红霞, 等. 可溶性晚期糖基化终末产物受体拮抗缺血/再灌注小鼠心肌纤维化［J］. 解剖学报, 2021, 52(5): 772-776.
［63］Lazo M, Halushka M K, Shen L, et al. Soluble receptor for advanced glycation end products and the risk for incident heart failure: the atherosclerosis risk in communities study［J］. Am Heart J, 2015, 170(5): 961-967.
［64］Raposeiras-Roubín S, Rodiño-Janeiro B K, Grigorian-Shamagian L, et al. Relation of soluble receptor for advanced glycation end products to predict mortality in patients with chronic heart failure independently of Seattle heart failure score［J］. Am J Cardiol, 2011, 107(6): 938-944.
［65］Zand Parsa A F, Nejati S, Esteghamati A. Is there a relationship between advanced glycation endproducts and soluble receptors of advanced glycation endproducts with the etiology and severity of congestive heart failure?［J］. Cardiology, 2015, 131: 294.
［66］Paradela-Dobarro B, Agra R M, Álvarez L, et al. The different roles for the advanced glycation end products axis in heart failure and acute coronary syndrome settings［J］. Nutr Metab Cardiovasc Dis, 2019, 29(10): 1050-1060.
［67］Koyama Y, Takeishi Y, Niizeki T, et al. Soluble receptor for advanced glycation end products (RAGE) is a prognostic factor for heart failure［J］. J Card Fail, 2008, 14(2): 133-139.
［68］Bangert A, Andrassy M, Müller A M, et al. Critical role of RAGE and HMGB1 in inflammatory heart disease［J］. Proc Natl Acad Sci U S A, 2016, 113(2): E155-E164.
［69］Simina-Ramona Selejan S R, Dahlem F, Hohl M, et al. Differential regulation of Receptor for Advanced Glycation End products(RAGE)in ischemic and post-inflammatory dilated cardiomyopathy［J］. Eur J Heart Fail, 2016, 18: 211.
［70］Leonardis D, Basta G, Mallamaci F, et al. Circulating soluble receptor for advanced glycation end product (sRAGE) and left ventricular hypertrophy in patients with chronic kidney disease (CKD)［J］. Nutr Metab Cardiovasc Dis, 2012, 22(9): 748-755.
［71］Geroldi D, Falcone C, Emanuele E, et al. Decreased plasma levels of soluble receptor for advanced glycation end-products in patients with essential hypertension［J］. J Hypertens, 2005, 23(9): 1725-1729.

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