RNA N6-methyladenosine modulates endothelial atherogenic responses to disturbed flow in mice

Atherosclerosis preferentially occurs in atheroprone vasculature where human umbilical vein endothelial cells (HUVECs) are exposed to disturbed flow. Disturbed flow is associated with vascular inflammation and focal distribution. Recent studies have revealed the involvement of epigenetic regulation in atherosclerosis progression. N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNA, but its function in endothelial atherogenic progression remains unclear. Here, we show that m6A mediates the EGFR signaling pathway during EC activation to regulate the atherosclerotic process. Oscillatory stress (OS) reduced the expression of METTL3, the primary m6A methyltransferase. Through m6A sequencing and functional studies, we determined that m6A mediates the mRNA decay of the vascular pathophysiology gene EGFR which leads to EC dysfunction. m6A modification of the EGFR 3'UTR accelerated its mRNA degradation. Double mutation of the EGFR 3'UTR abolished METTL3-induced luciferase activity. Adenovirus-mediated METTL3 overexpression significantly reduced EGFR activation and endothelial dysfunction in the presence of OS. Furthermore, TSP-1, an EGFR ligand, was specifically expressed in atheroprone regions without being affected by METTL3. Inhibition of the TSP-1/EGFR axis by using shRNA and AG1478 significantly ameliorated atherogenesis. Overall, our study revealed that METTL3 alleviates endothelial atherogenic progression through m6A-dependent stabilization of EGFR mRNA, highlighting the important role of RNA transcriptomics in atherosclerosis regulation.

The Possible Role of Herpesviruses in the Pathogenesis of Coronary Atherosclerosis

Cardiovascular diseases are still the dominant cause of death worldwide. Coronary artery disease (CAD) is the most common type of heart disease and the leading cause of death for both men and women. Coronary atherosclerosis underlies multiple clinical manifestations ranging from asymptomatic to stable angina, acute coronary syndrome, MI, heart failure, and sudden cardiac death. The prerequisites for a closer study of the pathogenesis of the atherosclerotic process were the development of atherosclerotic vascular lesions at a younger age and the rapid progression of the process. Currently, it is generally accepted that CAD is a multifactorial disease. Attention is drawn to hereditary disorders of the receptor apparatus, endothelial dysfunction, and lipid metabolism disorders. In addition, latent viral infections are one of the etiopathogenetic factors in the development of atherosclerosis. A number of scientific studies have confirmed the relationship between infectious agents and the development of atherosclerotic vascular lesions. The viral etiology of the development and progression of atherosclerosis is the subject of debate among scientists around the world.

Functional Active Genomics of Isoprene Biogenesis and resistance to cardiovascular diseases

The pathologic development of the atherosclerotic process is often associated with the metabolism of saturated and unsaturated fatty acid. Substitution of the saturated fatty acids in nutrition for polyunsaturated fatty acids is traditionally associated with the lowering of risk of coronary breaches rise. Understanding the molecular mechanisms of the atherosclerosis development and progress is very important for early diagnostic and effective medical treatment of the above-mentioned disease. After a thorough analysis of the data available on the pathological atherosclerotic process, we have come to the conclusion that this disease begins from vascular smooth muscle cell (VSMC) impaired function. In the basis of the atherosclerosis development lies isoprenes biogenesis breach, caused by cholesterol and the products of its metabolism. Atherosclerosis is a chronic inflammatory disease of the media wall of large- and medium-sized arteries. And endothelium injury is a consequence of the pathologic process progressing in myocytes. Metabolic problems have become so relevant that it is time to form a metabolic policy. Real target programs for the prevention of the development of metabolic diseases and their diagnostics in the early stages of development should be developed. But in order to achieve this goal, it is necessary to know the real molecular mechanism of development of the early stages of metabolic diseases. It is necessary to recognize that the research work on the metabolic problem was carried out mainly in the plane of the functionally-energy parameter and captures only the consequences of the pathological process. And the very reason and early stages of metabolic diseases remained hidden from us, as they are depending on the pathology in the plane Regulatory, Information, Coordination and Functional active bioenergy system.

Oxidative Stress in the Pathogenesis of Antiphospholipid Syndrome: Implications for the Atherothrombotic Process

Atherothrombosis is a frequent complication of the clinical history of patients with antiphospholipid syndrome (APS). Both atherothrombosis and APS are characterized by increased oxidative stress. Oxidative modifications are implicated in the formation of antiphospholipid antibodies, which in turn may favour the oxidative imbalance by increasing the production of reactive oxidant species (ROS) or by a direct interaction with pro-oxidant/antioxidant enzymes. As a result of these processes, APS patients suffer from an oxidative imbalance that may contribute to the progression of the atherosclerotic process and to the onset of ischemic thrombotic complications. The aim of this review is to describe mechanisms implicated in the formation of ROS in APS patients and their involvement in the atherothrombotic process. We also provide an overview of potential therapeutic approaches to blunt oxidative stress and to prevent atherothrombotic complications in these patients.

Emerging Nanoparticles in the Diagnosis of Atherosclerosis

Throughout the last few decades, cardiovascular research has substantially advanced our awareness of the atherosclerotic process, the molecular processes underlying the disease remain essentially unexplained. Atherosclerosis results from the imbalanced lipid metabolism and lipoproteins accumulation that results in the thickening of the artery walls, linked to most cardiovascular events, and also one of the foremost common causes of morbidity and mortality around the world. Despite the extensive investigation into the process of development and advancement of atherosclerotic lesions over the years, there is little information is available. The use and handling of nanotechnology on a molecular scale is a new approach to quantify the functional organization in nanometers. In medicine, it is capable to improve diagnostics, delivery of pharmaceuticals, treatment, and many areas of research, development, and clinical application. Medical nanotechnology or nanomedicine has demonstrated a growing trend in the reduction of costs and improve the efficiency of current medicines, diagnostic reagents, implants, etc. Nanomedicine overcomes certain problems of conventional drugs like drug toxicity and the required dose of the drug. Promising research has resulted in pre-clinical validation of nanoscale devices targeting cell and molecular components of atherosclerotic plaque in the past decade. This review paper will cover basic insights into the use of nanomedicine in atherosclerosis

Relationship between psychovegetative status dysfunction and markers of the early formation of the atherosclerotic process in flight personnel in the Far North

The aim of this work is studying the influence of the severity of dysfunctions on the part of the central and autonomic nervous systems on the atherosclerotic process in hypertension in flight crews with concomitant traditional factors of cardiovascular risk (abdominal obesity) serving in the Far North by the authors.Materials and methods. A clinical examination was carried out on 54 patients (men) aged from 33 to 42 years, from among the military personnel of the aviation personnel of the Northern Fleet naval aviation, the average age of the examined was 37.4±4.6 years. The following groups of patients were formed: 1st (n=26) — flight crew specialists serving in the Far North, with first degree abdominal obesity, first stage hypertension and moderate astheno-neurotic disorders (main group); 2nd (n=14) — flight crew specialists serving in the Far North, with first degree abdominal obesity, first stage hypertension in comorbidity with mild astheno-neurotic disorders; Group 3 (n=10) was represented by flight crew patients with the first stage of hypertension with initial manifestations of psychovegetative dysfunctions (control). We assessed the qualitative and quantitative paired correlations between the state of the psychological status, regulation of the neuropsychic adaptation system, markers of early formation of atherosclerosis, and indicators of the average daily blood pressure level.Results and their discussion. It was found that the severity of disorders of the asthenovegetative spectrum in the examined groups has a negative direct pathological effect on quantitative and qualitative paired correlations between indicators characterizing the state of psychophysiological status, markers of early formation of the atherosclerotic process, and values of average daily blood pressure monitoring. The results obtained make it possible to summarize that the more pronounced the disturbances in the functioning of the central and autonomic nervous systems in hypertension in persons from the flight crew, the more significant the shifts towards atherogenicity of indicators reflecting the activity of the atherosclerotic process and the more unfavorable outcome in the course of cardiovascular pathology in such patients.

SARS-CoV-2 and Atherosclerosis: Should COVID-19 Be Recognized as a New Predisposing Cardiovascular Risk Factor?

At the beginning of the COVID-19 pandemic, the lung was recognized as the main target organ; now, new evidence suggests that SARS-CoV-2 infection leads to vascular disease. In a previous review, we supposed a bidirectional link between endothelial dysfunction and COVID-19, identifying atherosclerosis as having a crucial role in its pathogenesis. Atherosclerosis with an existing endothelial dysfunction may worsen COVID-19 manifestations, leading to adverse outcomes, as largely reported. However, COVID-19 may be the trigger factor in the progression of the atherosclerotic process up to making it clinically manifest. The thrombotic complications can involve not only the atherosclerotic plaque, but also the durability of the surgical device implanted to treat a pre-existing coronary artery disease as recently reported. The burden of the disease makes necessary a long-term stratification of patients, revising drastically targeted therapy among others.

Gut Microbiome, Functional Food, Atherosclerosis, and Vascular Calcifications—Is There a Missing Link?

The gut microbiome is represented by the genome of all microorganisms (symbiotic, potential pathogens, or pathogens) residing in the intestine. These ecological communities are involved in almost all metabolic diseases and cardiovascular diseases are not excluded. Atherosclerosis, with a continuously increasing incidence in recent years, is the leading cause of coronary heart disease and stroke by plaque rupture and intraplaque hemorrhage. Vascular calcification, a process very much alike with osteogenesis, is considered to be a marker of advanced atherosclerosis. New evidence, suggesting the role of dietary intake influence on the diversity of the gut microbiome in the development of vascular calcifications, is highly debated. Gut microbiota can metabolize choline, phosphatidylcholine, and L-carnitine and produce vasculotoxic metabolites, such as trimethylamine-N-oxide (TMAO), a proatherogenic metabolite. This review article aims to discuss the latest research about how probiotics and the correction of diet is impacting the gut microbiota and its metabolites in the atherosclerotic process and vascular calcification. Further studies could create the premises for interventions in the microbiome as future primary tools in the prevention of atherosclerotic plaque and vascular calcifications.

Assessment of calcium antagonist therapy protective effect on the thickness of the intima-media complex in patients with arterial hypertension

Aim. To evaluate the connection of calcium antagonist (amlodipine) therapy with the dynamics of the intima-media complex thickness in patients with arterial hypertension (AH), depending on genetic polymorphism.Methods. The study included representatives of the indigenous nationality (the Shors) – 901 people, of which a group of 367 people with hypertension was identified. The prospective stage of observation included 234 people who did not receive antihypertensive therapy. Based on the prescription of calcium antagonists, patients with hypertension were divided into two groups. Gene polymorphism was tested by polymerase chain reaction.Results. In the Shor cohort, the regression of the intima-media complex thickness of the carotid arteries was observed more often in hypertensive patients who received calcium antagonists if to compare them with those who did not take the drug [OR = 2.30]. In addition, the decrease in the atherosclerotic process is associated with the genotype carriage: I/I of the ACE gene [OR = 9.42], T/C of the AGT gene [OR = 3.52], 4b/4b and 4b/4a of the eNOS gene [OR = 2.26 and OR = 3.75], C/C of the MTHFR gene [OR = 2.62].Conclusion. Pharmacogenetic aspects are valuable from the point of view of an individual approach and obtaining the most pronounced pharmacological response in order to slow down the processes of vascular wall remodeling in patients with hypertension.

Hol van a normális és a kóros vérnyomás közötti határ, és mi a terápiás cél a cardiovascularis és a renalis betegségekben?

Összefoglaló. Az irodalmi adatok arra utalnak, hogy a systolés vérnyomás értékének emelkedése már 110–115 Hgmm-től együtt jár az atherosclerosissal összefüggő elváltozások kialakulásával is és ezzel együtt a cardiovascularis és a renalis funkció romlásával. Az összefüggés exponenciális, de mértékét az életkor jelentősen befolyásolja. A kezelés során az elérendő vérnyomás célértéke a jelenlegi adatok alapján 120–130 Hgmm között helyezkedik el a 18–65 év közötti populációban; idősebb korban – különösen 80 év felett – ennél magasabb, a 130 Hgmm alatti érték elérése nem reális, de talán nem is szükséges. A leghelyesebb az egyéni vérnyomásprofil meghatározása, és számos befolyásoló tényezőt is figyelembe kell venni a páciens legmegfelelőbb kezeléséhez. A populáció egészségének javításához és megőrzéséhez az egyik legfontosabb és leggyakoribb cardiovascularis kockázati tényezőt, a magas vérnyomást időben fel kell fedezni, amihez a vérnyomást rendszeresen szükséges ellenőrizni, és ezzel párhuzamosan kell végezni a prevenciót célzó tevékenységeket (nevelés, oktatás, szűrés, egészségtudatos életmód) is. Orv Hetil. 2021; 162(34): 1351–1361. Summary. The data in the literature suggest that the increase in the value of systolic blood pressure from 110–115 mmHg leads to the development of atherosclerotic process and to the deterioration of cardiovascular and renal function. The correlation is initially linear, then above 140–150 mmHg it is already exponential, but it is also related to the progression of the age. The systolic target for therapy is between 120–130 mmHg in the population aged 18–65; in older ages – especially over 80 years – it is higher and reaching the value below 130 mmHg is unrealistic, and may even be not necessary. It is the best to determine the individual treatment, taking into account the individual blood pressure profile and the factors influencing the patient. In order to improve and maintain the health of the population – in addition to unknown hypertension – it is necessary to regularly monitor blood pressure and apply the known preventive methods (education, training, screening, etc). Orv Hetil. 2021; 162(34): 1351–1361.