Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : April 29, 2018
Accepted : May 16, 2018
Published online : June 30, 2018
doi:10.24659/gsr.5.2_82

Review article

Glycative stress and anti-aging: 8. Glycative stress and arteriosclerotic disease.
Masayuki Yagi, Yoshikazu Yonei
Anti-Aging Medical Research Center and Glycative Stress Research Center, Faculty of Life and Medical Sciences,
Doshisha University, Kyoto, Japan

Abstract

Arteriosclerotic disease is a generic term for arterial lesions characterized by thickening, hardening and remodeling of
the arterial wall. Under this term, three lesions are listed: atherosclerosis, arteriolosclerosis and Mӧnckeberg's medial calcificsclerosis. Among them, atherosclerosis is the most deeply associated with the onset of life-style diseases. In the processes andhistologic changes, cellular debris of necrosis accumulates in the intima of a blood vessel, which is referred to as atheroma
and fibrous capsule covers its surface layer. In this lesion, the oxidation and glycation of LDL (low-density lipoprotein) isinvolved in accumulation in endothelial cells in the formation of atheroma. Glycated-LDL is involved in the enhancement forexpression of inflammatory cytokine and cell adhesion factors, which are induced by the production of reactive oxygen andthe activation of protein kinase C (PKC) via bonding with receptors for advanced glycation end products (RAGE). Ruptureof fibrous capsules covering atheroma, malignant transformation, and hemorrhage are factors that promote the formation ofthrombin, which induces acute coronary syndrome and cerebral infarction. Apoptotic death of smooth muscle cells and foamcells around atheroma induces cytolysis and membranous vesicle is discharged into the extracellular matrix. Subsequently,hydroxyapatite is formed. When mineralization occurs, amorphous calcium is deposited in tissues. This vascular calcificationinduces arterial dysfunction, which is a risk factor of increased pulse pressure, cardiac stress, impaired peripheral circulation,
and also the destabilization of atherosclerosis.

KEY WORDS: advanced glycation end products (AGEs), atheroma, calcification

1. Introduction:
Definition of arteriosclerosis

Arteriosclerotic disease designates mainly cardiovasculardisease and cerebrovascular disease but is recognized as
multiple vessel diseases including peripheral arterial disease.
Therefore, arteriosclerosis involves a variety of risk factors,
hence comprehensive countermeasures are required for theprevention of atherosclerotic cardiovascular disease 1, 2).
Arteriosclerosis is a generic term for arterial lesions
characterized by thickening, hardening and remodeling of
the arterial wall. Under this term, three lesions are listed:atherosclerosis, arteriolosclerosis and Mӧnckeberg's sclerosis
with calcification. Among them, atherosclerosis is the mostdeeply associated with the onset of lifestyle-related diseases
and occurs in a relatively large elastic type artery. From theviewpoint of histology, atherosclerosis is a lesion where fatty
decay products of necrosis, which is referred to as atheroma,
accumulates in the intima of a blood vessel and fibrous capsulecovers its surface layer ( Fig. 1 ) 3). According to a guideline
Contact Address: Professor Masayuki Yagi, PhD
Glycative Stress Research Center,
Faculty of Life and Medical Sciences, Doshisha University
1- 3, Tatara Miyakodani, Kyotanabe, Kyoto, 610 - 0394 Japan
Phone/Fax: +81-774 - 65- 6394 E-mail: myagi@mail.doshisha.ac.jp
Co-author: Yonei Y, yyonei@mail.doshisha.ac.jp

of World Health Organization (WHO), atherosclerosis
is defined as “a lesion of the accumulation of lipid, acidmucopolysaccharide, blood-derived materials, fiber andcalcium deposition due to changes mainly in the intima.”

2. Atherosclerosis and AGEs

Multiple mechanisms are involved in the formation ofatheroma along with the progression of atherosclerosis. The
early stage in arteriosclerotic lesion is referred to as a fattystreak. A fatty streak is characterized by the deposition ofblood-derived lipid in the intima of a blood vessel, which
underwent fibrocellular thickening, the accumulation ofmacrophage-derived foam cells, and the infiltration of T
lymphocyte 4). This lesion is induced as follows: Low-density
lipoprotein (LDL) comprises of lipoprotein, especially one
molecule of apolipoprotein B (ApoB), which passes throughan endothelial cell from a blood vessel, and lipoids such as
cholesterol, phospholipid and triglyceride. LDL binds with_ 82 _Glycative Stress Research 2018; 5 (2): 082- 0 85(c) Society for Glycative Stress ResearchGlycative Stress ResearchFig. 1. Structures of the atherosclerosis.

The figure is adapted and modified from Reference 3.

an extracellular matrix or proteoglycan and accumulates inthe intima. When LDL is glycated, the glycated LDL is notrecognized by low density lipoprotein receptor (LDL-R) andaccumulates in endothelial cell. AGE-LDL is produced fromGly-LDL. AGE-LDL binds with receptors for advanced
glycation end products (RAGE), which are expressed invascular cells such as endothelial cells and smooth musclecells. The enhancement of inflammatory cytokine and celladhesion factor expression are induced via the productionof reactive oxygen species (ROS), the activation of protein
kinase C (PKC) and the activation of mitogen-activatedprotein kinase (MAPK). Consequently, in the endothelial
cells, the migration and proliferation of smooth muscle cells,
the abnormality of cells and the acceleration of oxidative
stress are induced. ROS produced by oxidative stress oxidizes
not only vascular wall cells but also glycated LDL. WhenGly-LDL is oxidized, lipid hydroperoxide is produced.
Furthermore, malondialdehyde (MDA) is produced as asecondary product. Glycation of LDL induces the productionof hexitollysine (HL). Meanwhile, under the existence of ROS,N ε - (carboxymethyl) lysine (CML) is formed from LDL.
Subsequently, LDL is oxidized, glycated and oxidatively
modified, and accumulates in the intima ( Fig. 2 ) 5). The
binding activities of oxidized LDL with collagen is greaterthan those of intact LDL, thus the oxidized LDL is retained
longer in the arterial wall 6). Glycated and oxidized LDL
accumulated in the intima, along with formed CML andoxidized phosphatidylcholine (OxPC) of lipoperoxide,

is uptaken in macrophage, which infiltrates the intima.
Subsequently, foam cells are formed from macrophages.
Contrarily, ApoB and pyrraline, which are types of AGEs,
are not uptaken in macrophage and are distributed in theextracellular matrix of the intima 7). Further, macrophagesecretes inflammatory cytokine such as tumor necrosis
factors of (TNF)-α, TNF-β and interleukin (IL) and growth
factors. Consequently, smooth muscle cells are transformed,
and the migration, proliferation and collagen production
are promoted. As proteolytic enzymes such as matrix
metalloproteinase (MMP) are secreted, deconstruction andrepair is repeated. As a consequence of these processes,
atheroma is formed in the intima of blood vessels.
Rupture of fibrous capsules covering atheroma are,malignant transformation and hemorrhage, promote theformation of thrombin, which induces acute coronary
syndrome and cerebral infarction.

3. Arterial calcification and AGEs
Atheroma with progressive atherosclerosis hascalcification. This is regarded as a final stage of the conditionin arterial wall degeneration and necrobiosis. Apoptotic deathof smooth muscle cells and foam cells around atheroma
induces cytolysis and membranous vesicle is discharged intothe extracellular matrix. Subsequently, hydroxyapatite is_ 83 _Glycative Stress and Arteriosclerotic Disease

Fig. 2. Atherogenic effects of glycation of LDL and HDL.

LDL; low density lipoprotein; HDL, high density lipoprotein; Gly-LDL, glycated LDL; Gly-HDL, glycated HDL; Gly-ox-LDL,oxidized glycated LDL; Gly-ox-HDL, oxidized glycated HDL. The figure is adapted from Reference 5.

formed. When mineralization occurs, amorphous calcium isdeposited in tissues.
Diabetes mellitus includes the acceleration of glycation,and the accumulation of AGEs in collagen of arterial walls.
Changes in molecular structure of AGE-collagen easily
induce calcification 3). For this reason, granular calcification
as an early stage lesion of Mӧnckeberg's arteriosclerosis isfound in tunica media of arteries in patients with diabetes.
CML localizes in calcified tunica media. CML is also
formed in arterial collagen, as was previously shown 8).
Patients with renal failure exclusively have calcification
along elastic fibers of an elastic type artery of the aorta. The
elevation of AGE-protein in serum, pentosidine, and alsointermediate products of glycation of dicarbonyl compounds,
such as CML, along with the dysbolism of calcium andphosphorus, are involved in arterial calcification in patientswith renal failure 9, 10). Renal failure induces the accumulationof AGEs and intermediates of AGEs and accelerates AGEs
formation, which is a vicious circle. Therefore, as sclerosis,
including atherosclerosis develops, calcification develops.
This vascular calcification induces arterial dysfunction,
which includes risk factors of increased pulse pressure,cardiac stress, impaired peripheral circulation, andalso atherosclerotic plaque destabilization. From theses
viewpoints, the inhibition of glycation can lead to thereduction of arterial calcification. There is a possibility thatthe inhibition of glycation can contribute to the prevention
and improvement of cardio vascular complications indiabetes and renal failure.

Acknowledgement

This work was partially supported by the JapaneseCouncil for Science, Technology and Innovation, SIP (ProjectID 14533567 ), “Technologies for creating next-generationagriculture, forestry and fisheries” (funding agency: Biooriented Technology Research Advancement Institution,NARO).

Conflict of Interest Statement_ 84 _The authors claim no conflict of interest in this study.

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