Dicarbonyl-Dependent Modification of LDL as a Key Factor of Endothelial Dysfunction and Atherosclerotic Vascular Wall Damage

Abstract

The review presents evidence that the main damage to the vascular wall occurs not from the action of “oxidized” LDL, which contain hydroperoxy acyls in the phospholipids located in their outer layer, but from the action of LDL particles whose apoprotein B-100 is chemically modified with low molecular weight dicarbonyls, such as malondialdehyde, glyoxal, and methylglyoxal. It has been argued that dicarbonyl-modified LDL, which have the highest cholesterol content, are particularly “atherogenic”. High levels of dicarbonyl-modified LDL have been found to be characteristic of some mutations of apoprotein B-100. Based on the reviewed data, we hypothesized a common molecular mechanism underlying vascular wall damage in atherosclerosis and diabetes mellitus. The important role of oxidatively modified LDL in endothelial dysfunction is discussed in detail. In particular, the role of the interaction of the endothelial receptor LOX-1 with oxidatively modified LDL, which leads to the expression of NADPH oxidase, which in turn generates superoxide anion radical, is discussed. Such hyperproduction of ROS can cause destruction of the glycocalyx, a protective layer of endotheliocytes, and stimulation of apoptosis in these cells. On the whole, the accumulated evidence suggests that carbonyl modification of apoprotein B-100 of LDL is a key factor responsible for vascular wall damage leading to atherogenesis and endothelial dysfunction. Possible ways of pharmacological correction of free radical processes in atherogenesis and diabetogenesis are also discussed.

Clearance and Utilization of Dicarbonyl-Modified LDL in Monkeys and Humans

“…It is firmly established that oxidative stress is an important etiological and pathogenic factor in atherosclerosis and diabetes mellitus [1][2][3][4][5][6]. The development of oxidative stress is paralleled with the augmented production of reactive oxygen species (ROS) and the downregulation of their utilization by the antioxidant enzyme systems in cells and tissues [1,[4][5][6].…”

“…It is firmly established that oxidative stress is an important etiological and pathogenic factor in atherosclerosis and diabetes mellitus [1][2][3][4][5][6]. The development of oxidative stress is paralleled with the augmented production of reactive oxygen species (ROS) and the downregulation of their utilization by the antioxidant enzyme systems in cells and tissues [1,[4][5][6]. The oxidative stress is manifested by the activation of free radical oxidation (FRO) processes in lipid-protein supramolecular complexes (biomembranes and lipoproteins), resulting in the accumulation of lipohydroperoxides, which are the primary products of polyene lipid FRO, whose downstream oxidative destruction culminates with the formation of malondialdehyde (MDA) [5,7].…”

“…The development of oxidative stress is paralleled with the augmented production of reactive oxygen species (ROS) and the downregulation of their utilization by the antioxidant enzyme systems in cells and tissues [1,[4][5][6]. The oxidative stress is manifested by the activation of free radical oxidation (FRO) processes in lipid-protein supramolecular complexes (biomembranes and lipoproteins), resulting in the accumulation of lipohydroperoxides, which are the primary products of polyene lipid FRO, whose downstream oxidative destruction culminates with the formation of malondialdehyde (MDA) [5,7]. Hyperlipidemia, an indispensible feature of atherogenesis, up-regulates FRO, resulting in the accumulation of primary and secondary FRO products in blood plasma [2,5,6].…”

“…The oxidative stress is manifested by the activation of free radical oxidation (FRO) processes in lipid-protein supramolecular complexes (biomembranes and lipoproteins), resulting in the accumulation of lipohydroperoxides, which are the primary products of polyene lipid FRO, whose downstream oxidative destruction culminates with the formation of malondialdehyde (MDA) [5,7]. Hyperlipidemia, an indispensible feature of atherogenesis, up-regulates FRO, resulting in the accumulation of primary and secondary FRO products in blood plasma [2,5,6]. The secondary products of polyene lipids FRO, exemplified by low molecular weight dicarbonyls such as MDA, can efficiently react with free ε-amino groups of lysine in B-100 apolipoprotein in low-density lipoproteins (LDL), which are the blood plasma lipids-transporting nanoparticles, thereby modifying their structure [2,5,6].…”

“…Hyperlipidemia, an indispensible feature of atherogenesis, up-regulates FRO, resulting in the accumulation of primary and secondary FRO products in blood plasma [2,5,6]. The secondary products of polyene lipids FRO, exemplified by low molecular weight dicarbonyls such as MDA, can efficiently react with free ε-amino groups of lysine in B-100 apolipoprotein in low-density lipoproteins (LDL), which are the blood plasma lipids-transporting nanoparticles, thereby modifying their structure [2,5,6]. Earlier studies by us and other researchers [8,9] have shown that chemically modified LDL, such as MDA-modified LDL, is captured by cultured macrophages together with the scavenger receptors, characterized by a far greater efficiency than that of non-oxidized LDL [8,9].…”