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

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.

Effect of Sulodexide on Circulating Blood Cells in Patients with Mild COVID-19.

Background. Despite the fact that COVID-19 usually manifests with severe pneumonia, there is a growing body of evidence that life-threatening multiorgan damage is caused by vascular and hemostatic abnormalities. Since there is no established therapy, assessing antithrombotics is indeed important. Sulodexide, a compound derived from porcine intestinal mucosa is a mixture of fast-moving heparin fraction (80%) and dermatan sulfate (20%), is approved in Europe and currently in trials for COVID-19 indication. Methods. This single-center, prospective, observational study included 28 patients with mild COVID-19 hospitalized in the Central Clinical Hospital of the Presidential Administration of the Russian Federation. Patients in the control group (n = 14) were treated using routine therapy according to current guidelines, while patients in the experimental group (n = 14) had the routine treatment supplemented with daily intravenous injections of sulodexide in 600-unit doses. Scanning electron microscopy was utilized to examine the blood specimens derived from the cubital vein at admission and at 10 days after hospitalization, which was approximately the average duration of patients' treatment in the hospital (11.6 ± 0.4 days). Results. Sulodexide significantly (by 40%) diminished the score of circulating endothelial cells, potentially indicating its antiviral endothelium-protective properties. It also prevented the extra activation of the platelets and the formation of erythrocytic sludges. Among patients in the control group, the share of activated platelets rose from 37 ± 5% to 45 ± 6% (p = 0.04) over the course of the study period, whereas among patients in the experimental group, the share of activated platelets remained practically unchanged (43 ± 6% vs. 38 ± 4%, p = 0.22). The score of erythrocytic sludges in the control group remained practically the same (4.8 ± 1.1 at admission vs. 3.9 ± 0.9 after 10 days, p = 0.67), whereas in the experimental group, it significantly decreased (from 5.7 ± 1.7 to 2.4 ± 0.9, p = 0.03). Conclusions. Sulodexide is able to defend endothelium, normalize blood, and, seemingly, prevent thrombosis. Therefore, it may be considered as a promising and effective agent for the treatment of patients with mild COVID-19. Broader randomized trials are needed to assess whether the observed findings will transform into sustained long-term clinical benefit.

Mild COVID-19 and Impaired Blood Cell-Endothelial Crosstalk: Considering Long-Term Use of Antithrombotics?

BACKGROUND: Current coronavirus disease 2019 (COVID-19) pandemic reveals thrombotic, vascular, and endothelial dysfunctions at peak disease. However, the duration, degree of damage, and appropriate long-term use of antithrombotic strategies are unclear. Most COVID data are yielded from random clinical observations or autopsy of postmortem samples, while precise blood cellular data in survivors are insufficient. METHODS: We analyzed erythrocytes, circulating endothelial cells, and echinocytes by electron microscopy and flow cytometry in patients with confirmed COVID-19 (n = 31) and matched healthy controls (n = 32) on admission and at hospital discharge. RESULTS: All patients experienced mild disease, none required pulmonary support, and all survived. Admission number of circulating endothelial cells was significantly (40-100 times) higher in COVID-19 patients. Cells were massively damaged by multiple fenestrae in membranes with diameter comparable to the size of supercapsid in SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus. COVID-19 also provoked formation of stacked aggregated erythrocytes capable of clogging microvascular bed and of diminishing oxygen supply. In some patients, such abnormalities persisted at hospital discharge revealing remaining intracellular penetration of SARS-CoV-2 where it may be replicated and returned to circulation. CONCLUSION: These observational and descriptive data suggest that persistent viral cell injury may cause blood vessel damage; their increased permeability resulted in tissue edema, inflammation, platelet activation, and augmented thrombosis. There is a residual blood cell damage following the acute phase in some COVID-19 survivors. Controlled outcome-driven trials are urgently needed for exploring optimal use of long-term antithrombotics and vascular protection strategies even after mild COVID-19.

Malondialdehyde as an Important Key Factor of Molecular Mechanisms of Vascular Wall Damage under Heart Diseases Development.

This mini review is devoted to a specific issue: the role of malondialdehyde (MDA)-a secondary product of free radical lipid peroxidation-in the molecular mechanisms of the formation of primary atherosclerotic vascular wall lesions. The principal difference between this review and the available literature is that it discusses in detail the important role in atherogenesis not of "oxidized" LDL (i.e., LDL particles containing lipohydroperoxides), but of LDL particles chemically modified by the natural low-molecular weight dicarbonyl MDA. To confirm this, we consider the data obtained by us earlier, indicating that "atherogenic" are not LDL oxidized as a result of free radical lipoperoxidation and containing lipohydroperoxy derivatives of phospholipids in the outer layer of particles, but LDL whose apoprotein B-100 has been modified due to the chemical reaction of terminal lysine residue amino groups of the apoB-100 with the aldehyde groups of the MDA (Maillard reaction). In addition, we present our original data proving that MDA injures endothelial glycocalyx that suppress the ability of the endothelium to control arterial tone according to changes in wall shear stress. In summary, this mini review for the first time exhaustively discloses the key role of MDA in atherogenesis.

Enoxaparin dose impacts blood cell phenotypes during mild SARS-CoV-2 infection: the observational single-center study.

Coronavirus disease 2019 (COVID-19) is associated with various hemostatic abnormalities requiring constant search for better delicate antithrombotic management in these high-risk patients. The choice and the optimal dose of anticoagulant is important, but unclear, especially for mild COVID-19. Enoxaparin has been tested in several COVID trials with mixed results regarding hard clinical outcomes including mortality. We analyzed clinical, laboratory data and changes in platelets, erythrocytes and leukocytes by scanning electron microscopy on admission and at hospital discharge in patients with confirmed COVID-19 treated with enoxaparin (n = 31) and matched healthy controls (n = 32) in a retrospective observational study. The data were triaged by enoxaparin dose comparing 40 mg/daily prophylactic enoxaparin dose (PED) with 80 mg/daily therapeutic (TED) regimens. All patients experienced mild disease, none required pulmonary support, and all survived. The impact of enoxaparin dose was prominent for platelets and erythrocytes, but less evident for leukocytes. PED was associated with significant platelet activation, diminished numbers of silent nonactive discoid cells, and increased number and size of platelet microaggregates with leukocyte involvement. In contrast, TED did not cause extra platelet activation, while circulating platelet microaggregates were smaller and lacking leukocytes in their construction. PED caused significant increase of erythrocyte-platelet aggregates formation, and numerically higher proportion of circulating echinocytes. TED was associated with significant decrease of rouleaux sludge formation compared to only some trend after PED. Changes in leukocytes were less dependent on enoxaparin dose. However, PED has been associated with enhanced aggregate formation in 7 out of 10 patients, while trap net formation has been decreased in 17 out of 21 TED patients. We conclude that over hospital stay TED was superior to PED in patients with mild COVID-19. The inability of PED to adequately protect major circulating blood cells is probably due to enhanced clearance or/and diminished bioavailability of enoxaparin during COVID. These retrospective observational small sample size data may be relevant to better understanding of the mixed results in controlled outcome-driven trials exploring optimal COVID-19 anticoagulant strategies.

Impact of olokizumab on platelets, leukocytes and erythrocytes during mild COVID-19.

No abstract present.

Malonyldialdehyde and glyoxal act differently on low-density lipoproteins and endotheliocytes.

Under some pathological conditions, the natural dicarbonyl compounds can accumulate in the blood. The examples are malonyldialdehyde (MDA) formed as a secondary product of lipid peroxidation of unsaturated fatty acids during atherosclerosis, and glyoxal (GOX), a homolog of MDA, which accumulates during glucose autoxidation in patients with diabetes mellitus. This study compared the influence of both dicarbonyl compounds on low-density lipoproteins (LDL) and the membrane of endotheliocytes. In comparison with GOX, MDA induced more pronounced changes in physical and chemical properties of LDL particles. On the other hand, GOX-modified LDL particles were more prone to oxidation and aggregation than MDA-modified LDL. Incubation of endotheliocytes with MDA increased cell mechanical stiffness in contrast to incubation with GOX, which decreased it.

Use of input impedance to determine changes in the resistance of arterial vessels at different levels in feline femoral bed.

In many studies, the functional state of vessels of different caliber was determined by fitting the lumped parameters of a mathematical model of the bed in order to fit the vascular input impedance (Z in) data. However, reliability of the results obtained in such a way remains uncertain. In this study, we employed a mathematical model with seven lumped parameters and Z in experimental data to analyze the distribution of resistance across the arterial bed of the hind limb in anesthetized cats, to test reliability of this distribution and to describe the process of ascending arterial dilation followed occlusion of iliac artery. The vascular bed was divided into three segments: large arteries, medium-sized arterial vessels and precapillary resistance vessels together with venous part of the bed. Based on the data of Z in measured in a wide frequency range (from 0 to 150 Hz) we showed that pharmacologically induced constriction and dilation of the arterial microvessels were reflected in the model by the changes in the resistance of distal precapillary vessels only, whereas the local constriction or dilation of femoral and iliac arteries as well as artificial stenosis of the femoral artery resulted exclusively in the changes of the resistance describing the state of large arteries. Using the input impedance method we could demonstrate and quantitatively describe the process of ascending arterial dilation during the post-occlusion (reactive) hyperemia. All these results prove that the model of vascular bed with seven lumped elements used in combination with input hydraulic impedance data can be an effective tool permitted to quantitatively analyze the functional state of arterial vessels of different caliber and to describe the changes in resistance of arterial vessels during vascular reactions.

Role of endothelium sensitivity to shear stress in noradrenaline-induced constriction of feline femoral arterial bed under constant flow and constant pressure perfusions.

The effect of shear stress at the endothelium in the attenuation of the noradrenaline-induced constriction of the femoral vascular bed perfused at a constant blood flow was investigated in 16 anesthetized cats. It is known that the adrenergic vasoconstriction of the femoral vascular bed is considerably greater at a constant pressure perfusion than at a constant blood flow. This difference may depend on the ability of the endothelium to relax smooth muscle in response to an increase in wall shear stress. Since the shear stress is directly related to the blood flow and inversely related to the third power of vessel diameter, vasoconstriction at a constant blood flow increases the wall shear stress that is the stimulus for smooth muscle relaxation opposing constriction. On the other hand, at a constant perfusion pressure, vasoconstriction is accompanied by a decrease in flow rate, which prevents a wall shear stress increase. To reveal the effect of endothelial sensitivity to shear stress, we compared noradrenaline-induced changes in total and proximal arterial resistances during perfusion of the hind limb at a constant blood flow and at a constant pressure in vessels with intact and injured endothelium. We found that in the endothelium-intact bed the same concentration of noradrenaline at a constant flow caused an increase in overall vascular peripheral resistance that was half as large as at a constant perfusion pressure. This difference is mainly confined to the proximal arterial vessels (arteries and large arterioles) whose resistance at a constant flow increased only 0.19 +/- 0.03 times compared to that at a constant pressure. The removal of the endothelium only slightly increased constrictor responses at the perfusion under a constant pressure (noradrenaline-induced increases of both overall and proximal arterial resistance augmented by 12%), while the responses of the proximal vessels at a constant flow became 4.7 +/- 0.4 times greater than in the endothelium-intact bed. A selective blockage of endothelium sensitivity to shear stress using a glutaraldehyde dimer augmented the constrictor responses of the proximal vessels at a constant flow 4.6-fold (+/-0.3), but had no significant effect on the responses at a constant pressure. These results are consistent with the conclusion that the difference in constrictor responses at constant flow and pressure perfusions depends mainly on the smooth muscle relaxation caused by increased wall shear stress.