Ablation of SAMD1 in Mice Causes Failure of Angiogenesis, Embryonic Lethality

Pathological retention of LDL in the intima is involved in atherosclerosis, although the retention mechanisms are not well-understood. Previously, we reported Sterile Alpha Motif Domain Containing 1 (SAMD1), a protein secreted by intimal smooth muscle cells in atherosclerotic lesions, appears to bind LDL in extracellular matrix around intimal cells. Fab-fragment inhibitors of apparently irreversible SAMD1/LDL binding reduced LDL retention in carotid injury models, but did not have a significant effect on early spontaneous lesion initiation. The normal function of SAMD1 is unknown, but it may have multiple epigenetic roles; our histology of mouse atherosclerosis models revealed extensive SAMD1 expression, possibly related to cell phenotype modulation and antigen presentation. For this report, we generated SAMD1-/-, SAMD1-/+, and SAMD1-/+ apoE-/- mice to further explore SAMD1's role in atherosclerosis. SAMD1 was found in tissues throughout the SAMD1+/+ and SAMD1-/+embryos. Homozygous loss of SAMD1 was embryonic lethal: at embryonic day 14, organs were partially developed and/or degraded; heads and brains were malformed; no blood vessels were observed; red blood cells were scattered and pooled, primarily near the embryo surface; and cell death was occurring. Development appeared normal in heterozygous SAMD1 embryos, but postnatal genotyping showed a reduced ability to thrive. Growth of atherosclerotic lesions in SAMD1-/+ apoE-/- after 35 weeks was not significantly less than in mice SAMD1+/+ apoE-/- mice.

Where the Action Is—Leukocyte Recruitment in Atherosclerosis

Atherosclerosis is the leading cause of death worldwide and leukocyte recruitment is a key element of this phenomenon, thus allowing immune cells to enter the arterial wall. There, in concert with accumulating lipids, the invading leukocytes trigger a plethora of inflammatory responses which promote the influx of additional leukocytes and lead to the continued growth of atherosclerotic plaques. The recruitment process follows a precise scheme of tethering, rolling, firm arrest, crawling and transmigration and involves multiple cellular and subcellular players. This review aims to provide a comprehensive up-to-date insight into the process of leukocyte recruitment relevant to atherosclerosis, each from the perspective of endothelial cells, monocytes and macrophages, neutrophils, T lymphocytes and platelets. In addition, therapeutic options targeting leukocyte recruitment into atherosclerotic lesions—or potentially arising from the growing body of insights into its precise mechanisms—are highlighted.

CD74 in Apoptotic Macrophages Is Associated with Inflammation, Plaque Progression and Clinical Manifestations in Human Atherosclerotic Lesions

The aim of this study was to investigate whether CD74 levels in atherosclerotic lesions are associated with inflammation, apoptosis, plaque severity, and clinical symptoms among patients with carotid atherosclerosis. We further studied whether CD74 expression is associated with apoptosis in macrophages induced by 7ketocholesterol (7keto). Sixty-one carotid samples (39 males and 22 females) were immunostained with macrophages, smooth muscle cells, CD74, ferritin, TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling), and thrombin receptors. Double immunocytochemistry of CD74 and caspase 3 or CD74 and Annexin V was performed on THP-1 macrophages exposed to 7keto. In human carotid plaques, CD74 expression is lesion-dependently increased and is associated with necrotic core formation and plaque rupture, clinical symptoms, macrophage apoptosis, ferritin, and thrombin receptors. CD74 levels were inversely correlated to high-density lipoproteins and statin treatment, and positively correlated to triglycerides. In THP-1 macrophages, 7keto induced a significant increase in levels of CD74, ferritin, and apoptotic cell death. This study suggests that CD74 in apoptotic macrophages is linked to inflammation and thrombosis in progression of human atherosclerotic plaques, lipid metabolism, and clinical manifestation in atherosclerosis. Surface CD74 in apoptotic macrophages and ferritin production induced by oxidized lipids may contribute to inflammation and plaque vulnerability in atherosclerosis.

Early and late outcomes of combined and staged surgeries in patients with concomitant atherosclerotic lesions of the coronary and brachiocephalic arteries

Objective. To study the early and late outcomes of surgical treatment of patients with concomitant atherosclerotic lesions of coronary and brachiocephalic arteries while choosing a treatment strategy based on the developed diff erentiated approach algorithm.Material and Methods. The study comprised 243 patients with combined atherosclerotic lesions of the coronary and carotid arteries examined during the period from 01.07.2014 to 01.01.2021. Patients underwent revascularization surgeries based on the algorithm for choosing the volume and stages of surgical intervention, which was previously developed in the Federal Center for Cardiovascular Surgery named after S.G. Sukhanov. A single-stage combined surgery of coronary artery bypass grafting (CABG) and carotid endarterectomy (CEE) was performed in 104 patients (42.8%); 139 patients (57.2%) received staged revascularization including 102 patients (73.4%) who received CABG as the fi rst step and 37 patients (26.6%) who received CEE as the fi rst step of surgery. The endpoints for both early and late results were death from all causes, stroke, transient ischemic attack (TIA), acute myocardial infarction (AMI), and combined endpoint that included all of the above. Average follow-up time was 41.1 ± 21.8 months.Results. No fatal outcomes were in any group during the early postoperative period. At the hospital stage, there were 5 cases (2.1%) of stroke, 1 case (0.4%) of TIA, and 3 cases (1.2%) of acute MI. Long-term results were evaluated in 225 patients (92.3%). The overall survival rate was 93.8%. There were 5 cases (2.4%) of MI, 11 cases (4.9%) of stroke, and 1 case (1.0%) of TIA. No signifi cant diff erences were observed in immediate and long-term endpoints between the groups of staged and combined interventions as compared to immediate (AMI: p = 0.680; TIA: p = 0.500; acute cerebrovascular events: p = 0.567; combined: p = 0.940) and long-term results (deaths: 0.860; AMI: p = 0.906; TIA: p = 0.528; acute cerebrovascular events: p = 0.378; combined: p = 0.669).Conclusion. Based on successful experience with treating the concomitant atherosclerotic lesions of the coronary and brachiocephalic arteries, the proposed algorithm allowed to perform safe procedures in both arterial basins and to achieve satisfactory results in in-hospital and long-term periods in the Federal Center for Cardiovascular Surgery named after S.G. Sukhanov (Perm).

T329S Mutation in the FMO3 Gene Alleviates Lipid Metabolic Diseases in Chickens in the Late Laying Period

The T329S mutation in flavin-containing monooxygenase 3 (FMO3) impairs the trimethylamine (TMA) metabolism in laying hens. The TMA metabolic pathway is closely linked to lipid metabolic diseases, such as atherosclerosis and fatty liver disease. We aimed to evaluate the effects of the T329S mutation in FMO3 on lipid metabolism in chickens during the late laying period. We selected 18 FMO3 genotyped individuals (consisting of six AA, six AT, and six TT hens) with similar body weight and production performance. The lipid metabolism and deposition characteristics of the laying hens with different genotypes were compared. The T329S mutation moderated the serum-lipid parameters in TT hens compared to those in AA and AT hens from 49 to 62 weeks. Furthermore, it reduced the serum trimethylamine N-oxide concentrations and increased the serum total bile acid (p < 0.05) and related lipid transporter levels in TT hens. Moreover, it significantly (p < 0.01) decreased atherosclerotic lesions and hepatic steatosis in TT hens compared to those in the AA and AT hens. Our findings may help improve the health status in laying hens during the late laying period.

NT-proBNP as an Additional Marker of Significant Coronary Atherosclerotic Lesions

Coronary artery disease (CAD) is the leading cause for morbidity and mortality both in Ukraine and in the world, so the relevance of this problem for the society is undeniable. The priority is still to study the factors that affect both more severe CAD in patients with chronic coronary syndrome and after myocardial revascularization. The aim. To investigate the patterns of correlation between blood level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and CAD severity, especially in patients with multivessel lesion, to confirm its status of a useful additional marker for assessing the condition of cardiovascular system and one of the instruments to affect the tactics of treatment. Materials and methods. The study is based on data obtained from a prospective analysis of 40 patients at the age of 51 to 82 years old from January to December 2019, whose complaints could indicate the CAD. All the patients underwent a comprehensive clinical and laboratory examination (complete blood count, biochemical blood test). The main instrumental examination method was coronary angiography; the patients were divided into 2 groups on the basis of the examination results. The quantitative degree of lesion was assessed using the SYNTAX Score for each patient. Results. The groups were comparable in terms of age, sex, and comorbidities. The groups differed significantly in terms of body mass index. Moreover, the groups differed in the level of the following biochemical markers: NT-proBNP (p=0.0001), cholesterol (p=0.02), low-density lipoproteins (p=0.009), creatinine (p=0.02), glomerular filtration rate (p=0.08). A significant correlation was found between the NT-proBNP level and the degree of CAD ρ=0.718 (p=0.0001). Conclusion. NT-proBNP significantly correlates with the SYNTAX Score and is the highest in the group of patients with multivessel coronary disease. This indicator requires further study as an additional marker for assessing the state of the cardiovascular system and can influence the choice of treatment.

Implication of miR-155-5p and miR-143-3p in the Vascular Insulin Resistance and Instability of Human and Experimental Atherosclerotic Plaque

Background: Cardiovascular diseases (CVDs) are the main cause of death in first world countries, being atherosclerosis, a recurring process underlying their apparition. MicroRNAs (miRNAs) are small non-coding RNAs that modulate the expression of their target proteins. Therefore, they have emerged as key players in diseases like cancer, diabetes, or CVDs.Methods: Apolipoprotein E-deficient (ApoE-/-) mice fed a standard type diet (STD) or high fat diet (HFD) for 8 and 18 weeks was compared to wild type (WT) STD-fed groups for the same time. 18 miRNAs were selected (from pubmed and GEO database) for their possible role in promoting atherosclerosis and were analysed by RT-qPCR in the aorta from the experimental model. Afterwards, the altered miRNAs in the aorta from 18 weeks-ApoE-/- mice were studied in human healthy aortic samples, human early aortic atherosclerotic plaques, and human advanced carotid atherosclerotic plaques. Results: From the 18 miRNAs analyzed, miR-155-5p was overexpressed and miR-143-3p was downregulated in mouse and human atherosclerotic lesions. In addition, a significant decrease of protein kinase B (AKT), target of miR-155-5p, and an increase of insulin-like growth factor type II receptor (IGF-IIR), target of miR-143-3p, were noted in aortic roots from ApoE-/- mice and in carotid plaques from ACA patients. Finally, both miRNAs were studied on vascular endothelial and smooth muscle cell lines. The overexpression of miR-155-5p reduced AKT levels and its phosphorylation in vascular smooth muscle cells. MiR-143-3p overexpression decreased IGF-IIR reducing apoptosis in vascular cells. Conclusions: Our results suggest that miR-155-5p and miR-143-3p may be implicated in insulin resistance and plaque instability by the modulation of their targets AKT and IGF-IIR, contributing to the progression of experimental and human atherosclerosis.Trial Registration: authorization numbers PFS09-007 and PI1442016.

A Novel Isoform of COL4A1 in the Regulation of Vascular Intercellular Communication

Vascular interventions have transformed the outlook towards improved patient-outcomes following atherosclerotic lesions