ReviewProtein glycation during aging and in cardiovascular disease☆
Graphical abstract
Introduction
Degenerative diseases like cardiovascular diseases are major diseases in the industrialized nations, especially in the elderly and will continue to play a central role as the dominant cause of death due to the continuously increasing numbers of aged people. In addition, cardiovascular diseases are long-term complications of people living with diabetes mellitus (DM), which often lead to a reduced life span [1], [2]. The International Diabetes Federation (IDF) estimated the global burden of DM with 366 million people worldwide suffering from the disease, and by 2030 this number will have risen to 552 million. This has been ascribed mainly to problems resulting from life style (http://www.idf.org/diabetesatlas/). It is of interest, which common mechanisms caused by aging and/or DM will affect the cardiovascular system. Degenerative diseases are mainly based on a life-long accumulation of molecular damages within molecules, cells and tissues. As long as this damage is not reflected by a phenotype or a disease, most of the people summarize this as a physiological aging process. On the other hand, at some stages, the aggrieved molecules like mutated DNA, oxidized lipids or glycated proteins will lead to reduced cell and organ function and at the end to chronic diseases. This was mentioned by Ed Lakatta s as: “age-associated changes in cardiac and vascular properties alter the substrate upon which cardiovascular disease is superimposed”. It was shown that the stroke volume index as well as the left ventricular ejection fraction is preserved in older persons at rest, whereas the acute cardiac output is reduced during exhaustive exercise [3]. The accumulation of damages seems to be responsible for the reduction in organ function, especially the functional reserve, which is needed when the organ is stressed. This is reflected by the New York Heart Association (NYHA) Functional Classification of the heart, a classification system of the extent of heart failure. It starts with limitations only at high physical activity, goes to shortness of breath and/or angina during ordinary activity and ends up with severe limitations and symptoms at rest, indicating increasing reduction in functional reserve. Patients with higher NYHA staging have a worse prognosis [4]. Indeed, reduced organ function and especially the reduced functional reserve, leading to a decrease in adaptation to any sort of stressor, is one of the hallmarks in human aging [5], and it is one explanation of the increased risk during cardiac surgery in the elderly as well [6].
One characteristic of the functional decrease associated with aging is an increase in stiffness and loss of elasticity in arteries and organs [7], which occurs mainly in tissues rich in extracellular matrix and long-lived proteins such as the vessels and the heart. An increase in stiffness and/or reduction in elasticity induces diastolic heart failure or high blood pressure in the elderly and was seen early in patients with diabetes. A major mechanism for increased stiffness with aging is the accumulation of advanced glycation endproducts (AGEs) in the extracellular matrix [8]. AGEs are formed during the nonenzymatic reaction between reducing sugars like glucose, fructose or other α-carbonyls and the amino group of proteins, lipids or nucleic acid to form Schiff base and Amadori products [2]. As the formation of AGEs is a slow reaction, it was for a long time believed that especially proteins with a slow turnover like the collagens within the extracellular matrix are the preferable targets of this reaction. This was compatible with the idea that a decreased uptake of carbohydrates into cells in DM leads to increased sugar concentration in the extracellular space and to more AGE-modified matrix proteins. Indeed, an accumulation of modified collagen was detected during aging and DM [9]. Most of the research focused therefore on the modification of extracellular matrix proteins like collagens. In view of the “glycation hypothesis” of aging including the pathogenesis of diabetic complications, AGE modifications change the structural and functional properties of proteins and reduce their susceptibility to catabolism. Bartling et al. indeed showed that modification of collagen by AGEs leads to a reduced degradability by metalloproteinases (MMPs) [10]. AGEs are shown to accumulate with aging and diabetes [11], [12], [13] and AGE deposits were demonstrated in atherosclerotic plaques and myocardium of patients with diabetes [14]. The mechanical stiffness of the vascular system and heart as a consequence of such alteration of collagen, elastin and laminin due to the formation of crosslinks between collagen fibers by AGEs was discussed [15]. Breakers of AGE-induced crosslinks like ALT-711 reverse the stiff phenotype of large arteries [16]. Furthermore AGEs could influence cardiac function by activating AGE receptors, mainly the receptor for advanced glycation endproducts (RAGE). The activation of this receptor by AGEs results in fibrosis, impaired calcium metabolism, and vasoconstriction in the cardiovascular system [17]. In addition, AGEs could induce an increase in oxidative stress which is also contributing to age associated decline in organ function.
Section snippets
Protein glycation
In 1912, the French scientist Louis Camille Maillard first observed a browning reaction by heating glycine and glucose [18]. This reaction, now called Maillard reaction, is not a single reaction, but a complex series of reactions between amino acids and reducing sugars and is the driving force of AGE formation. It occurs in body fluids and in all tissues, outside as well as inside cells. The paradigm for these reactions is the condensation of glucose with a lysine residue on a protein to a
Analysis of glycated proteins — problems and pitfalls
One of the major problems with the analysis of AGEs in a tissue is the sample preparation. As highly modified proteins are often cross-linked, it seems difficult to extract them from the tissue. A typical problem is the discrepancy between an increase in AGE-modified extracellular matrix, seen by histochemical staining, and no real difference on the basis of biochemical prepared protein lysates in a Western blot analysis. This can largely be explained by a typical collagen preparation. In most
The glycation reaction in biological systems
AGEs can have an impact on the function of biological systems by several means. Modifications on proteins can clearly alter structure, enzymatic activity and biological half-life [39], [40]. If DNA is modified the consequence can be mutations, and if membrane lipids are hit, this might affect transport and signaling processes. Last, but not least, AGEs can act through specific receptor molecules.
For several enzymes it has been shown that the presence of an AGE-modification alters, if not
AGEs and cardiovascular diseases
Patients especially with diastolic heart failure have decreased ventricular relaxation, and/or an increase in ventricular and arterial stiffness [91], [92]. Cardiovascular complications are the most important cause of morbidity and mortality and account for up to 70% of diabetic fatalities [93]. Regarding the heart, diastolic heart failure seems to be a major complication of patients with long lasting DM. Hyperglycemia as usually detected in DM leads to non-enzymatic glycation of proteins which
Clinical studies based on AGE degradation
AGE crosslink breakers such as ALT-711 are discussed to break AGE-based crosslinks between proteins and should reduce tissue stiffness. It has therefore been tested to improve the compliance in the cardiovascular system. In animal studies using for example experimental diabetes in rats or aged dogs, the crosslink breaker treatment effectively reduced age-related myocardial stiffness or reversed the diabetes induced increase of large artery stiffness [16], [116]. Positive results from studies
Glycation as a biomarker
AGEs are produced in the body and accumulate in the tissues with age. Many studies analyzed AGEs in easy accessible body fluids and tried to correlate these values with the age of the subjects or the disease state of patients. For example, in a follow-up study in 394 moderately to severely disabled women (≥ 65 years), women with elevated serum CML are at an increased risk of developing severe walking disability [131]. In the Baltimore longitudinal study of aging, serum CML was associated with
Conclusion
Pathophysiological and epidemiological studies indicated evidence for a link between accumulation of AGEs and degenerative diseases like heart failure. The data suggest that glycation of proteins and binding of such modified proteins to the respective receptors are related to the development and progression of atherosclerosis and diastolic heart failure. Targeting AGEs therapeutically will further prove this pathophysiological hypothesis and hopefully represent a new treatment strategy for
Conflict of interest
The author discloses any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations that could inappropriately influence, or be perceived to influence, the actual work.
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This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine.