The association of coronary artery disease and advanced glycation end-products

Corresponding Author:

Craig Basman
Department of Cardiovascular Medicine,
Lenox Hill Hospital,
Northwell Health,
New York,
NY, USA,
E-mail: cbasman@northwell.edu

Received date: July 08, 2021 Accepted date: July 22, 2021 Published date: July 29, 2021

Abstract

Traditional risk factors are insufficient to explain all cases of Coronary Artery Disease (CAD) in patients with Diabetes Mellitus (DM). Hyperglycemia is the hallmark feature of DM. An increase in the incidence of both micro-and macrovascular complications of diabetes has been observed with increased duration of hyperglycemia. This association persists even after glycemic control has been achieved, suggesting an innate mechanism of “metabolic memory.” Advanced Glycation End products (AGEs) are glycated proteins or lipoproteins that may serve as mediators of metabolic memory due to their increased production in the setting of hyperglycemia and generally slow turnover. Elevated AGE levels can lead to abnormal cross linking of extracellular and intracellular proteins disrupting their normal structure and function. Furthermore, activation of AGE receptors can induce complex signaling pathways leading to increased inflammation, oxidative stress, enhanced calcium deposition, and increased vascular smooth muscle apoptosis, contributing to the development of atherosclerosis. Through these mechanisms, AGEs and their receptors may play important roles in the development and progression of CAD. However, clinical studies regarding the role of AGEs and their receptors in advancing CAD are limited, with contradictory results. Further studies are needed to evaluate the utility of circulating and tissue AGE levels in identifying asymptomatic patients at risk for CAD or to identify patients who may benefit from invasive intervention.

Keywords

Advanced glycation end products • Atherosclerosis • Coronary artery disease • Glycated proteins • Hemoglobin A1c

Abbreviations

CAD: Coronary Artery Disease; DM: Diabetes Mellitus; AGEs: Advanced Glycation End products; HbA1c: Hemoglobin A1c; CML: Nϵ-(Carboxymethyl) Lysine; sRAGE: soluble AGE Receptor.

Introduction

While the risk of Coronary Artery Disease (CAD) is higher in patients with Diabetes Mellitus (DM), the causal link has not yet been established. Hyperglycemia alone may not account for this risk as some landmark diabetes trials have shown that intensive glycemic control does not reduce cardiovascular events compared to standard therapy[1-3] Other studies [4,5], however, indicated that long term improved glycemic control reduces the risk of acute coronary events. Advanced Glycation End-products (AGEs), a heterogeneous class of glycated proteins and lipoproteins, have been associated with the development of atherosclerosis [6-10]. AGEs have been linked to a variety of pathological states, including chronic kidney disease and Alzheimer’s disease.

In individuals with diabetes, AGEs have been independently associated with cardiovascular morbidity and mortality [11,12]. The purpose of this review article is to analyze the relationship of AGEs and CAD.

What are AGEs and their receptors?

AGEs are a heterogeneous class of glycated proteins and lipoproteins. AGE accumulation can occur through endogenous synthesis or exogenous delivery through dietary intake. Though there are many AGEs, the most studied are hemoglobin A1c (HbA1c), glycated albumin, pentosidine, Nϵ-(carboxymethyl)lysine (CML) and their soluble receptor, sRAGE. AGEs can accumulate in nearly every tissue including brain, heart, eye, and kidney, binding to many extracellular and intracellular proteins in a variety of cell types. Activation of receptor for AGE (RAGE) by AGE binding initiates complex signaling pathways. Both AGEs and RAGE levels have been associated with atherosclerosis in patients with and without DM [13-15].

Association of AGEs and CAD

Evidence suggests that serum and tissue AGE levels may predict both the presence and the burden of CAD. Kerkeni, et al. found that pentosidine, not CML, was higher in patients with CAD irrespective of diabetic status (diabetic population; p=0.032 and non-diabetic population; p=0.002) [16]. In a cross-sectional analysis, Lu, et al. found that elevated glycated albumin and reduced sRAGE levels correlated with the severity of CAD and progression of atherosclerosis in patients with DM [17]. Kiuchi, et al. found that circulating AGE levels were higher in diabetic patients with obstructive CAD than non-obstructive CAD [18]. However, our group has previously published conflicting results, whereby AGE and sRAGE levels did not significantly correlate with the presence or degree of obstructive CAD [19]. Table 1 summarizes the studies analyzing the relationships between AGE levels and CAD.

Table 1: Studies investigating the relationship between AGEs and CAD.

Association of HbA1c and CAD

HbA1c has been identified as an independent predictor of CAD burden. Even, in patients without diabetes, a high-normal HbA1c level has been linked with an increased risk of CAD [6,20,21]. Additionally, HbA1c is also an independent risk factor for mortality in non-diabetic patients [22]. Previous results published by our group also found that elevated HbA1c levels correlate with the burden of CAD in both diabetic and non-diabetic patients [19]. This association is important not only because it may help identify patients at risk for cardiovascular events, but also because in patients presenting with acute coronary syndrome, a higher HbA1c may be associated with worse outcomes [23]. In one study, for every 1% increase in HbA1c level there was a 24% increase in mortality among non-diabetic patients presenting with ST elevation myocardial infarction. Interestingly, HbA1c level did not impact mortality among diabetic patients in this study [24], but in the larger Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction trial, HbA1c was an independent predictor of mortality among individuals with diabetes [25]. Table 2 lists a summary of trials investigating the link between HbA1c and outcomes among patients with ACS.

Table 2: Studies investigating the relationship between HbA1c and CAD.

As data accumulates, the association between HbA1c and cardiovascular events/outcomes is becoming clearer [26]. Yet, it remains unclear why this relationship exists. One hypothesis suggests that as a long half-life protein, HbA1c may be involved in a chronic inflammatory response resulting in accelerated atherosclerosis.

Mechanism of Cardiovascular Disease Induced by AGE/ RAGE Pathway

The pathogenic effects of AGE occur via several mechanisms including:

1) Modification of extracellular proteins

2) Modification of intracellular proteins

3) The binding to cell surface RAGE and activation of signaling cascades

Modification of extracellular proteins

AGEs can modify the structure of extracellular proteins such as collagen, elastin and laminin. This alters the protein function and may induce an inflammatory response. After these proteins become glycosylated, they may crosslink with other extracellular proteins and become resistant to proteolytic digestion [27], and increase vascular stiffness (or in the myocardium would result in impaired relaxation) [28]. Similarly, glycation of LDL molecules alters their shape which inhibits their re-uptake by LDL receptors. After LDL is unable to be cleared from the circulation it becomes oxidized and triggers the formation of foam cells (resulting in atherosclerosis) [29].

Modification of intracellular proteins

The accumulation of AGES in the endoplasmic reticulum causes impairment of normal protein folding. Intracellular AGEs bind to mitochondrial proteins that are involved in the electron transport system. This results in a decrease in adenosine triphosphate synthesis and production of reactive oxygen species [30]. In the myocardium, these intracellular AGEs alter calcium homeostasis and result systolic dysfunction [31].

Activation of signaling cascade

The AGE/RAGE axis activation generates a signaling cascade that results in the initiation of an inflammatory response [7]. The activation of RAGE results in translocation of NFκβ to the cell nucleus whereby it enhances expression of inflammatory cytokines (including IL-6, TNFα, TGF-β, and vascular adhesion molecules). These cytokines result in vascular inflammation (through stimulation of fibotic, proliferative and thrombogenic pathways) [7]. The AGE/RAGE axis also produces reactive oxygen species through NFκβ mediated upregulation. AGEs can also directly inactivate nitric oxide (which has a wide range of vascular properties including regulation of local cell growth, modulation of vascular tone and protection of blood vessels from reactive oxygen species) [7].

Potential Therapies

There has been multiple studies (both in vitro and animal) showing that reducing AGE levels may lead to a reduction in micro and macro-vascular DM complications. Reduction of these levels has been achieved through several mechanisms. There are compounds that inhibit AGE formation through anti-oxidant properties. The use of compounds such as aminoguanidine in rodents has resulted in a reduction in atherosclerotic plaque and improvement in myocardial function [32]. However, safety concerns such as nephrotoxicity exist for these compounds in humans [33]. Another way to reduce AGE formation is with sRAGE infusions. Infusion of sRAGE (or RAGE inhibitors) has been shown to reduce atherosclerotic burden in rodents, however to our knowledge these have not been tried in humans yet [34]. Lastly, reducing the dietary consumption of AGEs (or reducing intestinal absorption through the use of compounds such as sevelamer carbonate) has been shown to reduce HbA1c [7].

Discussion

There are several available therapies used for DM and cardiovascular disease that may reduce AGE levels by impacting the AGE/RAGE axis. Atorvastatin not only decreases LDL levels, but may increase esRAGE levels, thereby decreasing the accumulation of AGEs [35]. Rosiglitazone has also been shown to reduce esRAGE levels [36], and other oral hypoglycemics such as metformin and pioglitazone can block AGE formation [37]. Glucagon-like peptide-1 agonists may decrease RAGE expression, and linagliptin (a DPP4 inhibitor) suppresses activation of the AGE/RAGE axis [38]. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers significantly attenuate AGE production [39-42].

Conclusion

Evidence supporting the role of AGEs in the progression of CAD in patients with and without DM continues to accumulate. While the literature has controversial results among various AGEs, the association of HbA1c and CAD development is strong. Additionally, an elevated HbA1c portends a poorer prognosis in patients that present with acute coronary events. Given the increasing evidence supporting a role for AGEs in promoting cardiovascular events, development of therapeutic agents aimed at reducing circulating AGE concentrations (or blocking of RAGE activation) may improve outcomes. Continued investigation and further studies are required.

Conflicts of Interest

The authors declare they have no competing interests.

Funding Statement

No funding was received related to the writing and publication of this manuscript.

Acknowledgements

Not applicable.

References

1. Buse JB, Friedewald WT, Bigger JT, et al. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: Design and methods. Am J Cardiol. 99(12):  21-33 (2007).
2. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 358(24): 2560-72 (2008).
3. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 360(2): 129-39 (2009).
4. Gubitosi-Klug RA, Lachin JM, Backlund JYC, et al. Intensive diabetes treatment and cardiovascular outcomes in type1 diabetes: The DCCT/EDIC study 30-year follow-up. Diabetes Care. 39(5): 686-93 (2016).
5. Holman RR, Paul SK, Bethel MA, et al. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 359(15): 1577-89 (2008).
6. Tada Y, Yano S, Yamaguchi T, et al. Advanced glycation end products-induced vascular calcification is mediated by oxidative stress: Functional roles of NAD(P)H-oxidase. Horm Metab Res. 45(4): 267-72 (2013).
7. Fishman SL, Sonmez H, Basman C, et al. The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: A review. Mol Med. 24(1): 59 (2018).
8. Flier JS, Underhill LH, Brownlee M, et al. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 318(20): 1315-21 (1988).
9. Takata T, Sakasai-Sakai A, Ueda T, et al. Intracellular toxic advanced glycation end-products in cardiomyocytes may cause cardiovascular disease. Sci Rep. 9(1): 2121 (2019).
10. Kosmopoulos M, Drekolias D, Zavras PD, et al. Impact of advanced glycation end products (AGEs) signaling in coronary artery disease. Biochim Biophys Acta Mol Basis Dis. 1865(3): 611-619 (2019).
11. Egaña-Gorroño L, López-Díez R, Yepuri G, et al. Receptor for Advanced Glycation End Products (RAGE) and mechanisms and therapeutic opportunities in diabetes and cardiovascular disease: Insights from human subjects and animal models. Front Cardiovasc Med. 7: 37 (2020).
12. Nin JW, Jorsal A, Ferreira I, et al. Higher plasma levels of advanced glycation end products are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: A 12-year follow-up study. Diabetes Care. 34(2): 442-7 (2011).
13. Koyama H, Shoji T, Yokoyama H, et al. Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol. 25(12): 2587-93 (2005).
14. Genuth S, Sun W, Cleary P, et al. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes. 54(11): 3103-11 (2005).
15. Monnier VM, Sell DR, Strauch C, et al. The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes. J Diabetes Complications. 27(2): 141-9 (2013).
16. Kerkeni M, Weiss IS, Jaisson S, et al. Increased serum concentrations of pentosidine are related to presence and severity of coronary artery disease. Thromb Res. 134(3): 633-8 (2014).
17. Lu L, Pu LJ, Zhang Q, et al. Increased glycated albumin and decreased esRAGE levels are related to angiographic severity and extent of coronary artery disease in patients with type 2 diabetes. Atherosclerosis. 206(2): 540-5 (2009).
18. Kiuchi K, Nejima J, Takano T, et al. Increased serum concentrations of advanced glycation end products: A marker of coronary artery disease activity in type 2 diabetic patients. Heart. 85(1): 87-91 (2001).
19. Basman C, Fishman SL, Avtanski D, et al. Glycosylated hemoglobin, but not advanced glycation end products, predicts severity of coronary artery disease in patients with or without diabetes. Metabolism Open. 7: 100050 (2020).
20. Hong LF, Li XL, Guo YL, et al. Glycosylated hemoglobin A1c as a marker predicting the severity of coronary artery disease and early outcome in patients with stable angina. Lipids Health Dis. 13(1): 89 (2014).
21. Garg N, Moorthy N, Kapoor A, et al. Hemoglobin A1c in nondiabetic patients: An independent predictor of coronary artery disease and its severity. Mayo Clin Proc. 89(7): 908-16 (2014).
22. Liu Y, Yang YM, Zhu J, et al. Prognostic significance of hemoglobin A1c level in patients hospitalized with coronary artery disease. A systematic review and meta-analysis. Cardiovasc Diabetol. 10: 98 (2011).
23. Cicek G, Uyarel H, Ergelen M, et al. Hemoglobin A1c as a prognostic marker in patients undergoing primary angioplasty for acute myocardial infarction. Coron Artery Dis. 22(3): 131-7 (2011).
24. Gustafsson I, Kistorp CN, James MK, et al. Unrecognized glycometabolic disturbance as measured by hemoglobin A1c is associated with a poor outcome after acute myocardial infarction. Am Heart J. 154(3): 470-6 (2007).
25. Malmberg K, Norhammar A, Wedel H. Glycometabolic state at admission: Important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction. Long-term results from the diabetes and insulin-glucose infusion in acute myocardial infarction (DIGAMI) study. Circulation. 99(20): 2626-32 (1999).
26. Saleem T, Mohammad KH, Abdel-Fattah MM, et al. Association of glycosylated haemoglobin level and diabetes mellitus duration with the severity of coronary artery disease. Diab Vasc Dis Res. 5(3): 184-9 (2008).
27. Bailey AJ. Molecular mechanisms of ageing in connective tissues. Mech Ageing Dev. 122(7): 735-755 (2001).
28. Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens. 21(1): 3-12 (2003).
29. Cai W, He JC, Zhu L, et al. High levels of dietary advanced glycation end products transform low-density lipoprotein into a potent redox-sensitive mitogen-activated protein kinase stimulant in diabetic patients. Circulation. 110(3): 285-291 (2004).
30. Adamopoulos C, Farmaki E, Spilioti E, et al. Advanced glycation end-products induce endoplasmic reticulum stress in human aortic endothelial cells. Clin Chem Lab Med. 52(1): 151-160 (2014).
31. Bidasee KR, Nallani K, Yu Y, et al. Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/calcium-release channels. Diabetes. 52(7): 1825-36 (2003).
32. Forbes JM, Yee LT, Thallas V, et al. Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis. Diabetes. 53(7): 1813-23 (2004).
33. Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol. 24(1): 32-40 (2004).
34. Ha CH, Kim S, Chung J, et al. Inhibitory effect of soluble RAGE in disturbed flow-induced atherogenesis. Int J Mol Med. 32(2): 373-80 (2013).
35. Lu L, Peng WH, Wang W, et al. Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats. J Zhejiang Univ Sci B. 12(8): 652-9 (2011).
36. Tan KCB, Chow WS, Tso AWK, et al. Thiazolidinedione increases serum soluble receptor for advanced glycation end-products in type 2 diabetes. Diabetologia. 50(9): 1819-1825 (2007).
37. Rahbar S, Natarajan R, Yerneni K, et al. Evidence that pioglitazone, metformin and pentoxifylline are inhibitors of glycation. Clin Chim Acta. 301(1-2): 65-77 (2000).
38. Yamagishi S, Fukami K, Matsui T. Crosstalk between advanced glycation end products (AGEs)-receptor RAGE axis and dipeptidyl peptidase-4-incretin system in diabetic vascular complications. Cardiovasc Diabetol. 14: 2 (2015).
39. Miyata T, van Ypersele de Strihou C, Ueda Y, et al. Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: Biochemical mechanisms. J Am Soc Nephrol. 13(10): 2478-87 (2002).
40. Kanauchi M, Tsujimoto N, Hashimoto T. Advanced glycation end products in nondiabetic patients with coronary artery disease. Diabetes Care. 24(9): 1620-3 (2001).
41. Basta G, Berti S, Cocci F, et al. Plasma N-ε-(carboxymethyl)lysine levels are associated with the extent of vessel injury after coronary arterial stenting. Coron Artery Dis. 19(5): 299-305 (2008).
42. Chowdhury TA, Lasker SS. Elevated glycated haemoglobin in non-diabetic patients is associated with an increased mortality in myocardial infarction. Postgrad Med J. 74(874): 480-1 (1998).