Opinion: On the Way towards the New Paradigm of Atherosclerosis

Abstract

Atherosclerosis is a multicausal disease characterized by the formation of cholesterol-containing plaque in the pronounced intima nearest to the heart’s elastic-type arteries that have high levels of blood circulation. Plaques are formed due to arterial pressure-induced damage to the endothelium in areas of turbulent blood flow. It is found in the majority of the Western population, including young people. This denies the monogenic mechanism of atherogenesis. In 1988, Orekhov et al. and Kawai et al. discovered that the presence of atherogenic (modified, including oxidized ones) LDLs is necessary for atherogenesis. On the basis of our discovery, suggesting that the overloading of enterocytes with lipids could lead to the formation of modified LDLs, we proposed a new hypothesis explaining the main factors of atherogenesis. Indeed, when endothelial cells are damaged and then pass through the G2 phase of their cell cycle they secrete proteins into their basement membrane. This leads to thickening of the basement membrane and increases its affinity to LDL especially for modified ones. When the enterocyte transcytosis pathway is overloaded with fat, very large chylomicrons are formed, which have few sialic acids, circulate in the blood for a long time, undergo oxidation, and can induce the production of autoantibodies. It is the sialic acids that shield the short forks of the polysaccharide chains to which autoantibodies are produced. Here, these data are evaluated from the point of view of our new model.

Role of Endothelial Regeneration and Overloading of Enterocytes with Lipids in Capturing of Lipoproteins by Basement Membrane of Rat Aortic Endothelium

“…Earlier, we showed that in newborn rats, when the GC is overloaded, the chylomicrons were delayed in the post-Golgi compartment positive for LAMP2, a marker of lysosomes and late endosomes [ 80 ]. Since we were familiar with the contradiction of desialilyation of modified LDLs [ 5 ], we checked whether in adult animals, after the enterocyte overloading with lipids, post-Golgi carriers pass through LAMP2-positive compartments. To test the hypothesis that desialylation of ApoB and superficial lipids of chylomicrons may take place due to alterations of post-Golgi transport, we studied enterocytes of the small intestine taken from rats that were fed with a large amount of lipids into the stomach.…”

“…On the other hand, a rather high incidence of atherosclerosis in vegans (although to a lesser extent than in meat eaters) suggests that atherogenesis is not limited to increased cholesterol intake alone. Moreover, many people consume eggs and meat in high concentrations, and they do not develop atherosclerosis [ 4 , 5 ].…”

“…Of interest, oxidized LDL is not detected in the blood (reviewed by [ 8 ]). However, enlarged chylomicrons formed in the lipid overloaded enterocytes circulate in the blood longer and can undergo oxidation [ 4 , 5 ]. In contrast, Tertov et al [ 9 ] concluded that the oxidation of LDLs in blood and food is not important for atherogenesis.…”

“…This hypothesis postulated that the initiating event in the atherogenic process was some form of overt injury to the intimal endothelial lining, induced by toxic substances or altered hemodynamic forces. Focal endothelial desquamation induces platelet adhesion and the localized release of platelet-derived growth factors, inducing the proliferation and phenotypic modulation of medial smooth muscle cells, thus, generating a fibromuscular plaque [ 5 , 18 ]. In the human aorta fixed with perfusion immediately after death due to mechanical injury, we observed endothelial cells (ECs) with cilia and multinuclear ECs and small areas of endothelial detachment in the areas with turbulent blood flow [ 19 ].…”

“…Various methods of de-endothelization were used to model the process of endothelial regeneration. These influences include the drying of ECs [ 41 ]; using catheters to destroy the endothelium; injecting hypotonic solutions or air into the insulating area of blood vessels; local freezing of blood vessel walls; various chemical [ 4 , 5 ] and mechanical compression of the vessel [ 42 ]. The process of regeneration of the aortic endothelium after mechanical damage is described in detail by Schwartz’s and Reidy’s groups [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], and the description of similar data after cryoinjury was performed by Malczak and Buck [ 43 ] and us [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ] more than 35 years ago.…”