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Background: Coronary artery disease (CAD) has become a dominant economic and health burden worldwide, and the role of autophagy in CAD requires further clarification. In this study, we comprehensively revealed the association between autophagy flux and CAD from multiple hierarchies. We explored autophagy-associated long noncoding RNA (lncRNA) and the mechanisms underlying oxidative stress-induced human coronary artery endothelial cells (HCAECs) injury. Methods: (1) Autophagy-related proteins including LC3, p62, Beclin1, ATG5, and ATG7 were immunohistochemical stained in coronary specimens; (2) The levels and function of autophagy in the HCAEC oxidative stress model were evaluated using western blot (WB), transmission electron microscopy (TEM), and mRFP-GFP-LC3 adenovirus transfection experiments; (3) The competing endogenous RNA (ceRNA) network of lncRNA LUCAT1/hsa-miR-6776-5p/LRRC25 axis was constructed and validated; (4) The expression levels of above autophagy-related RNAs in peripheral blood mononuclear cells (PBMCs) were verified by qPCR, and their diagnostic performance was subsequently analyzed using receiver operating characteristic (ROC) analysis. Results: (1) The expression of LC3, Beclin1, ATG5, and ATG7 demonstrated a consistent decline whereas p62 expression exhibited an opposite increase as atherosclerosis progressed; (2) Autophagy levels was significantly elevated in HCAECs under oxidative stress, while inhibition of the initial stage of autophagy with 3-MA exacerbated cellular damage; (3) The lncRNA LUCAT1/hsa-miR-6776-5p/LRRC25 axis was established through bioinformatic prediction and validated by dual-luciferase reporter assay, which resulted in a significant decrease in autophagy levels in HCAECs; (4) In total, p62, ATG7, lncRNA LUCAT1 and LRRC25 were validated as robust diagnostic biomarkers for CAD. Conclusions: Our results delineated the dynamic disruption of the autophagy landscape during the progression of human coronary atherosclerosis and identified the lncRNA LUCAT1/hsa-miR-6776-5p/LRRC25 axis, uncovered through transcriptomic profiling, as a protective mechanism against endothelial cell injury through autophagy activation. Furthermore, we recognized p62, ATG7, lncRNA LUCAT1, and LRRC25 as dependable autophagy-related diagnostic biomarkers in circulating PBMCs, correlating with CAD severity. Collectively, Our findings furnish novel insights into the intricate autophagy landscape at various levels of coronary atherosclerosis and propose potential diagnostic biomarkers, and a theoretical foundation for managing CAD patients. [ABSTRACT FROM AUTHOR]

The article discusses the 32nd CEA symposium held in Würzburg, Germany, focusing on the biology of carcinoembryonic antigen cell adhesion molecules (CEACAMs). It explores the diverse roles of CEACAMs in pathogen-host interactions, immunity, cancer biology, atherogenesis, metabolism, and reproductive biology. The symposium also delves into the potential applications of CEACAMs in cancer diagnosis and therapy, liver disease, transplantation, endothelial signaling, platelet function, and pregnancy. Various laboratories presented research findings on the role of CEACAMs in different biological processes, highlighting their significance in various health and disease contexts. [Extracted from the article]

Aging plays a pivotal role in the pathogenesis of cerebral small vessel disease (CSVD), contributing to the onset and progression of vascular cognitive impairment and dementia (VCID). In older adults, CSVD often leads to significant pathological outcomes, including blood–brain barrier (BBB) disruption, which in turn triggers neuroinflammation and white matter damage. This damage is frequently observed as white matter hyperintensities (WMHs) in neuroimaging studies. There is mounting evidence that older adults with atherosclerotic vascular diseases, such as peripheral artery disease, ischemic heart disease, and carotid artery stenosis, face a heightened risk of developing CSVD and VCID. This review explores the complex relationship between peripheral atherosclerosis, the pathogenesis of CSVD, and BBB disruption. It explores the continuum of vascular aging, emphasizing the shared pathomechanisms that underlie atherosclerosis in large arteries and BBB disruption in the cerebral microcirculation, exacerbating both CSVD and VCID. By reviewing current evidence, this paper discusses the impact of endothelial dysfunction, cellular senescence, inflammation, and oxidative stress on vascular and neurovascular health. This review aims to enhance understanding of these complex interactions and advocate for integrated approaches to manage vascular health, thereby mitigating the risk and progression of CSVD and VCID. [ABSTRACT FROM AUTHOR]

Macrophage infiltration and accumulation in the atherosclerotic lesion are associated with plaque progression and instability. Depletion of macrophages from the lesion might provide valuable insights into plaque stabilization processes. Therefore, we assessed the effects of systemic and local macrophage depletion on atherogenesis. To deplete monocytes/macrophages we used atherosclerosis‐susceptible Apoe−/− mice, bearing a MaFIA (macrophage‐Fas‐induced‐apoptosis) suicide construct under control of the Csf1r (CD115) promotor, where selective apoptosis of Csf1r‐expressing cells was induced in a controlled manner, by administration of a drug, AP20187. Systemic induction of apoptosis resulted in a decrease in lesion macrophages and smooth‐muscle cells. Plaque size and necrotic core size remained unaffected. Two weeks after the systemic depletion of macrophages, we observed a replenishment of the myeloid compartment. Myelopoiesis was modulated resulting in an expansion of CSF1Rlo myeloid cells in the circulation and a shift from Ly6chi monocytes toward Ly6cint and Ly6clo populations in the spleen. Local apoptosis induction led to a decrease in plaque burden and macrophage content with marginal effects on the circulating myeloid cells. Local, but not systemic depletion of Csf1r+ myeloid cells resulted in decreased plaque burden. Systemic depletion led to CSF1Rlo‐monocyte expansion in blood, possibly explaining the lack of effects on plaque development. [ABSTRACT FROM AUTHOR]

Atherosclerosis is an age‐related pathological process associated with elevated levels of legumain in plaques and plasma. However, the underlying mechanisms remain unclear. The aim of this study was to investigate the role of legumain in the progression of atherosclerotic plaques, with a particular focus on functional and phenotypic changes in CD4+ T cells. Apolipoprotein E‐deficient (Apoe−/−) mice were crossed with legumain‐deficient (Lgmn−/−) mice to generate Lgmn−/−Apoe−/− mice. CD4+ T cells accumulated in the atherosclerotic plaques of Apoe−/− mice fed a high‐fat diet. Deletion of legumain attenuated the deposition of CD4+ T cells in plaques and reduced the number of atherosclerotic lesions. The levels of CD4+ T cells in the blood, lymph nodes, and spleen were decreased in Lgmn−/− mice. Transcriptomic analysis revealed that the deletion of legumain decreased the differentiation, survival, and function of CD4+ memory T cells by suppressing the T cell receptor (TCR) signaling pathway. These changes are accompanied by the downregulation of the antiapoptotic protein B‐cell lymphoma 2 (Bcl‐2) and the reduced release of interleukin (IL)‐2 and interferon (IFN)‐γ. These results suggest that legumain deficiency may play a role in the development of atherosclerosis by impairing the survival, proliferation, and function of CD4+ T cells. Inhibition of legumain activity may be an innovative therapy for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Background. Diabetes mellitus causes fasting hyperglycemia and dyslipidemia, and exposure of diabetics to aluminium can aggravate these effects, since aluminium exposure also causes prediabetic hyperglycemia and dyslipidemia. The effect has not been previously demonstrated in an animal model. Aim. Objective of the study was to determine the extent of aggravation of dyslipidemia after subchronic oral exposure of diabetics (type 1 model in rat) to aluminium chloride.Method. Forty adult male rats (weighing 189–285 g) were divided into four groups of ten rats each: Control group (CG); Aluminium chloride (Al) treated group (AG); Diabetic group (DG); Al-treated-diabetic group (ADG). Diabetes was induced by single intramuscular injection of aqueous alloxan monohydrate (100 mg/ml) at 120 mg/kg in DG and ADG. Each rat in the Al-treated groups (AG and ADG) was orally administered with aqueous aluminium chloride (100 g/L) daily (50 mg/kg; 12.5% of LD50) by gavage for 28 days. Fasting blood glucose (FBG) and serum total cholesterol (TC), triglyceride (TG) and high density lipoprotein cholesterol (HDLc) concentrations were determined. Low density lipoprotein cholesterol (LDLc) and atherogenic index of plasma (AIP) were calculated with formulae. Results. Diabetic hyperglycemia was maintained in DG and did not differ from ADG on day 7–21, but was higher (p < 0.05) on day 28 in association with aggravated dyslipidemia characterized by increases in TG, TC, LDLc, AIP and decrease in HDLc. Conclusion. Subchronic aluminium exposure in diabetics aggravated hyperglycemia and dyslipidemia with AIP elevation by 34%, suggesting an exaggeration of risk of atherogenesis, atherosclerosis and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Over 50% of patients who take statins are still at risk of developing atherosclerotic cardiovascular disease (ASCVD) and do not achieve their goal LDL-C levels. This residual risk is largely dependent on triglyceride-rich lipoproteins (TRL) and their remnants. In essence, remnant cholesterol-rich chylomicron (CM) and very-low-density lipoprotein (VLDL) particles play a role in atherogenesis. These remnants increase when lipoprotein lipase (LPL) activity is inhibited. ApoCIII has been thoroughly studied as a chief inhibitor and therapeutic options to curb its effect are available. On top of apoCIII regulation of LPL activity, there is a more precise control of LPL in various tissues, which makes it easier to physiologically divide the TRL burden according to the body's requirements. In general, oxidative tissues such as skeletal and cardiac muscle preferentially take up lipids during fasting. Conversely, LPL activity in adipocytes increases significantly after feeding, while its activity in oxidative tissues decreases concurrently. This perspective addresses the recent improvements in our understanding of circadian LPL regulations and their therapeutic implications. Three major tissue-specific lipolysis regulators have been identified: ANGPTL3, ANGPTL4, and ANGPTL8. Briefly, during the postprandial phase, liver ANGPTL8 acts on ANGPTL3 (which is released continuously from the liver) to inhibit LPL in the heart and muscle through an endocrine mechanism. On the other hand, when fasting, ANGPTL4, which is released by adipocytes, inhibits lipoprotein lipase in adipose tissue in a paracrine manner. ANGPTL3 inhibitors may play a therapeutic role in the treatment of hypertriglyceridemia. Several approaches are under development. We look forward to future studies to clarify (a) the nature of hormonal and nutritional factors that determine ANGPTL3, 4, and 8 activities, along with what long-term impacts may be expected if their regulation is impaired pharmacologically; (b) the understanding of the quantitative hierarchy and interaction of the regulatory actions of apoCIII, apoAV, and ANGPTL on LPL activity; (c) strategies for the safe and proper treatment of postprandial lipemia; and (d) the effect of fructose restriction on ANGPTL3, ANGPTL4, and ANGPTL8. [ABSTRACT FROM AUTHOR]

Aims: Endothelial inflammation is crucial in the initiation and progression of atherosclerosis, whereas cholesterol crystals (CCs) play a key role in atherogenesis. However, the effects and origination of CCs on endothelial inflammation are not well understood. Results: In the present study, we found that CCs appeared in the subendothelial space of the partially ligated carotid artery only 1 week after Western diet feeding, which was before immune cell infiltration. In vitro, CCs were generated by human aortic endothelial cells (HAECs) upon low-density lipoprotein treatment. These endothelial cell (EC)-derived CCs increased the expression of intercellular cell adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1). Mechanistic studies demonstrated that CC-induced pyroptosis was critical for endothelial inflammation. Knockdown of gasdermin D (GSDMD) inhibited CC-induced endothelial inflammation, attenuated plaque progression, and decreased macrophage content. Accordingly, the inhibition of GSDMD reduced the CC-induced increase of VCAM1 and ICAM1 in HAECs. Furthermore, CC-mediated pyroptosis was found to be caspase-1 (CASP1)-dependent. Inhibition of CASP1 also reduced endothelial inflammation and attenuated plaque progression. The expression of GSDMD was increased in human atherosclerotic plaques. These findings identify that EC-derived CCs may be an important driving force in the pathogenesis of atherosclerosis. Innovation: This study uncovered a new understanding that CC-induced pyroptosis contributes to endothelial inflammation in early atherogenesis. Conclusion: Targeting endothelial GSDMD or CASP1 contributes to the repression of vascular inflammation and atherogenesis. Antioxid. Redox Signal. 41, 201–215. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic condition that is the main underlying cause of cardiovascular disease. Inflammation is one of the key factors in the pathogenesis of atherosclerosis and its complications. This review explains an up-to-date understanding of the immunological mechanisms of atherogenesis and biomarkers of inflammation, as well as available treatments for low-intensity chronic inflammation. Information is provided on the perspective directions of anti-inflammatory therapy for atherosclerosis being studied.

Simple Summary: Glycolipid metabolic disorders (GLMDs) result from imbalances in glycolipid levels, leading to various health issues, including obesity, diabetes, liver problems, nerve and muscle complications, and cardiovascular and kidney diseases. This study explores the connection between GLMDs, oxidative stress, and chronic inflammation, which exacerbate these conditions. GLMD originates from disruptions in glucose and fat metabolism, often associated with hormone regulation and insulin resistance. These disruptions cause the accumulation of harmful molecules, triggering inflammation in multiple organs. Key molecules, such as advanced glycation end products (AGEs) and sphingosine-1-phosphate (S1P), play significant roles in this process. Understanding these relationships is essential for developing better treatments, reducing illness and mortality rates, lowering healthcare costs, and improving quality of life. Glycolipid metabolic disorders (GLMDs) are various metabolic disorders resulting from dysregulation in glycolipid levels, consequently leading to an increased risk of obesity, diabetes, liver dysfunction, neuromuscular complications, and cardiorenal vascular diseases (CRVDs). In patients with GLMDs, excess caloric intake and a lack of physical activity may contribute to oxidative stress (OxS) and systemic inflammation. This study aimed to review the connection between GLMD, OxS, metainflammation, and the onset of CRVD. GLMD is due to various metabolic disorders causing dysfunction in the synthesis, breakdown, and absorption of glucose and lipids in the body, resulting in excessive ectopic accumulation of these molecules. This is mainly due to neuroendocrine dysregulation, insulin resistance, OxS, and metainflammation. In GLMD, many inflammatory markers and defense cells play a vital role in related tissues and organs, such as blood vessels, pancreatic islets, the liver, muscle, the kidneys, and adipocytes, promoting inflammatory lesions that affect various interconnected organs through their signaling pathways. Advanced glycation end products, ATP-binding cassette transporter 1, Glucagon-like peptide-1, Toll-like receptor-4, and sphingosine-1-phosphate (S1P) play a crucial role in GLMD since they are related to glucolipid metabolism. The consequences of this is system organ damage and increased morbidity and mortality. [ABSTRACT FROM AUTHOR]

The thymus represents a primary organ of the immune system, harboring the generation and maturation of T lymphocytes. Starting from childhood, the thymus undergoes involution, being replaced with adipose tissue, and by an advanced age nearly all the thymus parenchyma is represented by adipocytes. This decline of thymic function is associated with compromised maturation and selection of T lymphocytes, which may directly impact the development of inflammation and induce various autoinflammatory disorders, including atherosclerosis. For a long time, thymus health in adults has been ignored. The process of adipogenesis in thymus and impact of thymic fat on cardiometabolism remains a mysterious process, with many issues being still unresolved. Meanwhile, thymus functional activity has a potential to be regulated, since islets of thymopoeisis remain in adults even at an advanced age. The present review describes the intricate process of thymic adipose involution, focusing on the issues of the thymus' role in the development of atherosclerosis and metabolic health, tightly interconnected with the state of vessels. We also review the recent information on the key molecular pathways and biologically active substances that may be targeted to manipulate both thymic function and atherosclerosis. [ABSTRACT FROM AUTHOR]

Purpose of Review: Low-density lipoprotein (LDL) poses a risk for atherosclerotic cardiovascular disease (ASCVD). As LDL comprises various subtypes differing in charge, density, and size, understanding their specific impact on ASCVD is crucial. Two highly atherogenic LDL subtypes—electronegative LDL (L5) and Lp(a)—induce vascular cell apoptosis and atherosclerotic changes independent of plasma cholesterol levels, and their mechanisms warrant further investigation. Here, we have compared the roles of L5 and Lp(a) in the development of ASCVD. Recent Findings: Lp(a) tends to accumulate in artery walls, promoting plaque formation and potentially triggering atherosclerosis progression through prothrombotic or antifibrinolytic effects. High Lp(a) levels correlate with calcific aortic stenosis and atherothrombosis risk. L5 can induce endothelial cell apoptosis and increase vascular permeability, inflammation, and atherogenesis, playing a key role in initiating atherosclerosis. Elevated L5 levels in certain high-risk populations may serve as a distinctive predictor of ASCVD. Summary: L5 and Lp(a) are both atherogenic lipoproteins contributing to ASCVD through distinct mechanisms. Lp(a) has garnered attention, but equal consideration should be given to L5. [ABSTRACT FROM AUTHOR]

Purpose of Review: In this review, we explore the intriguing and evolving connections between bacterial extracellular membrane nanovesicles (BEMNs) and atherosclerosis development, highlighting the evidence on molecular mechanisms by which BEMNs can promote the athero-inflammatory process that is central to the progression of atherosclerosis. Recent Findings: Atherosclerosis is a chronic inflammatory disease primarily driven by metabolic and lifestyle factors; however, some studies have suggested that bacterial infections may contribute to the development of both atherogenesis and inflammation in atherosclerotic lesions. In particular, the participation of BEMNs in atherosclerosis pathogenesis has attracted special attention. Summary: We provide some general insights into how the immune system responds to potential threats such as BEMNs during the development of atherosclerosis. A comprehensive understanding of contribution of BEMNs to atherosclerosis pathogenesis may lead to the development of targeted interventions for the prevention and treatment of the disease. [ABSTRACT FROM AUTHOR]

The level of cytokine expression was measured in human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells exposed to 500 ng/ml alkylating mutagen mitomycin C (MMC) and 5 μM atorvastatin. It was found that treatment of MMC-exposed HCAEC with atorvastatin decreased secretion of macrophage migration inhibitory factor (MIF), IL-8, and IL8 gene expression, but increased the expression of SERPINE1 gene encoding the PAI-1 protein. In atorvastatin-treated HITAEC, the concentration of MIF protein and the expression of the IL8 and SERPINE1 genes were reduced. We can conclude that atorvastatin prevents proinflammatory activation of endothelial cells cultured under conditions of genotoxic load. However, the molecular mechanisms of this effect require further research. [ABSTRACT FROM AUTHOR]

Plasminogen activator inhibitor-1 (PAI-1) has a significant role in fibrinolysis, atherogenesis, cellular senescence, and chronic inflammation. OSA (obstructive sleep apnea) leads to increased PAI-1 levels and the development of cardiovascular disease (CVD). The aim of this study was to determine the effects of CPAP therapy on coagulation parameters and PAI-1 in patients with severe OSA. This prospective, controlled study enrolled 57 patients who were newly diagnosed with severe OSA, 37 of whom had had good CPAP adherence after 6 months of therapy (usage of the device for at least 4 h per night), and their data were analyzed. The analysis showed a statistically significant increase in D-dimer values before CPAP therapy (415 (316.5–537.5)) vs. after therapy (499 (327–652)), p = 0.0282, and a decrease in fibrinogen values (3.665 ± 0.752 before CPAP therapy vs. 3.365 ± 0.771 after therapy, p = 0.0075)). PAI-1 concentration values before and after CPAP therapy did not differ significantly (17.35 ± 7.01 ng/mL before CPAP therapy vs. 17.42 ± 6.99 ng/mL after therapy, p = 0.9367). This study shows a tendency for fibrinolytic capacity to improve in patients with OSA after CPAP therapy, although PAI-1 levels did not differ significantly. [ABSTRACT FROM AUTHOR]

Integral indicators of systemic endotoxemia (SEE): the level of endotoxin (ET) and the concentration of antibodies against the hydrophobic (AB-LPS-PHOB) and hydrophilic (AB-LPS-PHIL) forms of the lipopolysaccharide molecule (LPS) in the general circulation, can be used to determine the risk category of the development and progression of atherosclerosis whose dynamics is an objective marker of aging rate. The comparison of images of the structure of the brachiocephalic artery wall in dynamics with changes in blood parameters is one of the most successful models for monitoring the atherosclerotic process in the clinical setting. In total, 42 subjects without recognized risk factors for the progression of atherosclerosis were examined at baseline and after 1.5–2 years. It was found that lipid profile indicators, such as the concentration of total cholesterol, low- and high-density lipoproteins, triglycerides, and the atherogenic index were of no prognostic value. While in the group with progression of damage to the arterial wall, an increase in the ET concentration and a decrease in the AB-LPS-PHOB and AB-LPS-PHIL concentrations were noted. In the group with regression of atherosclerotic changes, on the contrary, there was an AB increase against the background of a decrease in the ET concentration. A prospective study revealed an extremely important fact of a decrease in the LPS concentration in the blood of patients with positive dynamics of morphological manifestations of atherosclerosis, indicating both the reversibility of the atherosclerotic process and the involvement of ET in atherogenesis. This is a real way of extending the life span of an individual, which shows the perspective of how to achieve this goal, which is antiendotoxin therapy. [ABSTRACT FROM AUTHOR]

Mitomycin C (MMC)-induced genotoxic stress can be considered to be a novel trigger of endothelial dysfunction and atherosclerosis—a leading cause of cardiovascular morbidity and mortality worldwide. Given the increasing genotoxic load on the human organism, the decryption of the molecular pathways underlying genotoxic stress-induced endothelial dysfunction could improve our understanding of the role of genotoxic stress in atherogenesis. Here, we performed a proteomic profiling of human coronary artery endothelial cells (HCAECs) and human internal thoracic endothelial cells (HITAECs) in vitro that were exposed to MMC to identify the biochemical pathways and proteins underlying genotoxic stress-induced endothelial dysfunction. We denoted 198 and 71 unique, differentially expressed proteins (DEPs) in the MMC-treated HCAECs and HITAECs, respectively; only 4 DEPs were identified in both the HCAECs and HITAECs. In the MMC-treated HCAECs, 44.5% of the DEPs were upregulated and 55.5% of the DEPs were downregulated, while in HITAECs, these percentages were 72% and 28%, respectively. The denoted DEPs are involved in the processes of nucleotides and RNA metabolism, vesicle-mediated transport, post-translation protein modification, cell cycle control, the transport of small molecules, transcription and signal transduction. The obtained results could improve our understanding of the fundamental basis of atherogenesis and help in the justification of genotoxic stress as a risk factor for atherosclerosis. [ABSTRACT FROM AUTHOR]

Atherosclerosis and coronary artery disease are the leading causes of disability and mortality among the population. Genotoxic stress can be potentially considered as a new trigger of endothelial dysfunction underlying the pathogenesis of these diseases. This research was aimed to the study of molecular and genetic markers of genotoxic stress-induced endothelial dysfunction in normolipidemic Wistar rats. The study was carried out on male Wistar rats injected intravenously (tail vein) with the alkylating mutagen mitomycin C (MMC) at a dose of 0.5 mg/kg body weight (experimental group) or 0.9% NaCl solution (control group) three times a week for a month. Genotoxic stress in animals was assessed using a micronucleus assay in polychromatophilic erythrocytes (PCE); endothelial dysfunction was identified by assessing the expression of Vcam1, Icam1, Sele, Selp, Il6, Ccl2, Cxcl1, Mif, Vwf, Serpine1, Plau, Plat, Klf2, Klf4, Nfe2l2, Nos3, Snai1, Snai2, Twist1, Zeb1, Cdh5, and Cdh2 genes in the endothelial monolayer of the descending aorta. Rats of the experimental group developed pronounced genotoxic stress, as evidenced by a more than threefold increase in the frequency of micronucleated PCE and a decreased proportion of PCE in the total pool of erythrocytes analyzed. Gene expression profiling showed that rats of the experimental group exhibited a pro-inflammatory activation of the endothelium, accompanied by increased expression of Vcam1, Icam1, Selp, Il6, Ccl2 and Cxcl1 genes, as well as impaired endothelial mechanotransduction characterized by decreased expression of Klf2 and Klf4 genes. Thus, MMC-induced genotoxic stress in normolipidemic Wistar rats is associated with the two key pathogenic links of endothelial dysfunction and can be considered as one of its triggers. [ABSTRACT FROM AUTHOR]

In recent decades, understanding the molecular mechanisms leading to cerebral aneurysm development has been limited. Advances in molecular biology now suggest a plausible explanation, rooted in a chronically unbalanced high hemodynamic environment. Molecular evidence from human and animal intracranial aneurysm specimens indicates a common pathway, where hemodynamic stresses on the endothelium play a pivotal role. This results in endothelial dysfunction, initiating a cascade of inflammatory vessel wall remodeling and degenerative changes. Notably, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activated in response to turbulent flow, upregulates inflammation-related genes, contributing to aneurysm formation. Further elucidation of NF-κB's role in hemodynamic stress-induced upregulation and its impact on structural remodeling holds potential for understanding and addressing cerebral aneurysm formation and progression.NF-κB is essential for initiating inflammatory responses in endothelial cells, and its activation is influenced by fluid flow variations. Laminar WSS leads to a decline in signaling to NF-κB, while disrupted WSS increases nuclear localization. NF-κB expression is upregulated in zones susceptible to atherogenesis, but the full activation of NF-κB depends on supplementary components, such as inflammatory cytokines. NF-κB is activated in various cell types, including smooth muscle cells, macrophages, and endothelial cells, and plays a role in intracranial aneurysmal formation. Research shows that human atherosclerotic lesions include activated NF-κB, and mouse studies show a correlation between regions prone to aneurysmal formation and elevated NF-κB components. NF-κB plays a crucial role in intracranial aneurysmal formation by regulating enzymes that generate inflammatory lipid mediators. It also regulates monocyte chemoattractant protein-1, a chemokine essential for drawing monocytes during atherosclerotic lesion formation. NF-κB also regulates adhesion molecules in response to inflammation signals, which are correlated with the progression of aneurysmal formation in mouse models. Tumor necrosis factor alpha has been implicated in the activation of NF-κB, correlating with the development of cerebral aneurysms. TNF-alpha, a proinflammatory cytokine, is associated with inflammation and apoptosis in vascular diseases such as atherosclerosis and aneurysms. It mediates endothelial dysfunction characterized by increasing inflammatory cell recruitment across the vessel endothelium. TNF-alpha has been found to be upregulated in unruptured cerebral aneurysms compared with ruptured cerebral aneurysms, suggesting that TNF-alpha initiates early formation and growth of cerebral aneurysms but not sustained development leading to rupture. The prostaglandin E2 pathway has also been implicated in the genesis of cerebral aneurysms through the activation of NF-κB. PGE2, derived from arachidonic acid, acts on prostaglandin E receptor subtype 2, the factor capable of activating downstream NF-κB in the arterial wall. Blockade of both EP2 and COX-2 inhibition inhibits NF-κB activation and subsequent intracranial aneurysmal formation. In conclusion, wall shear stress can induce COX-2 and EP2 expression in cultured endothelial cells, potentially leading to the formation and maintenance of a chronic inflammatory process within the arterial wall, eventually succumbing to intracranial aneurysm formation. Endothelial dysfunction is a cornerstone pathognomic event in the initiation of cerebral aneurysm development. It refers to the upregulation of specific proinflammatory genes by the vascular endothelium through the transcription factor NF-κB and is responsible for the induction of adhesion and matrix remodeling molecules such as VCAM and MCP. It serves as a pathological link connecting the influence of abnormal wall shear stress and the attendant downstream inflammatory reaction in the arterial wall. The infiltration of inflammatory cells into the vessel wall is a pivotal hallmark in the genesis of nascent cerebral aneurysms. Leukocytes initially participate in the acute inflammatory process, secreting proteases that degrade the extracellular matrix, leading to vessel wall remodeling and aneurysm formation. Later, macrophages become the predominant inflammatory cell in the intracranial aneurysm wall contributing to aneurysmal development through the synthesis and release of proinflammatory cytokines and specific proteases such as matrix metalloproteinases that impair the integrity of the extracellular matrix. Inhibition of tissue inhibitors of matrix metalloproteinase facilitates cerebral aneurysm development by upregulating MMP activity. Inhibiting NF-κB P50 expression and activation decreases the likelihood of IA formation, while higher NF-κB activation associates with an increase in IA formation. Treatments that prevent the development, growth, and rupture of IAs hinder the mRNA expression, protein levels, and/or phosphorylation of NF-κB P65, indicating the significant role of NF-κB stimulation in the development and rupture of IAs. Inhibiting or suppressing NF-κB activation in specific cell types has yielded intriguing outcomes, such as reducing the occurrence of IA formation in macrophages but not in endothelial cells. Smooth muscle cells (SMCs) may also play a role in IA development and progression, suggesting that a single cellular source of NF-κB activation appears less likely in IA development and progression. [ABSTRACT FROM AUTHOR]

Summary: Significant acute cardiovascular, metabolic, and endocrine changes have been traced to short-lasting cold water immersion (CWI); however, the long-term impact of recurrent CWI on atherogenesis, lipid parameters, and fat distribution has not yet been studied. The goal of this study was to investigate the alleged protective effect. A total of 35 healthy volunteers were monitored for a period of 5 months during which the CWI was performed under standardized conditions (three times per week for 7–10 min, without neoprene equipment). Volunteers with measured weight or muscle mass increases of more than 5% were ineligible. An analogous control group (N = 30) was included. At the onset and completion of the study, blood samples were obtained, and clinical assessments took place. PCSK9 and hsCRP levels were measured together with other lipid-related and non-lipid-related indicators. Carotid intima-media thickness test (cIMT) and echo-tracking for the identification of arterial stiffness (PWV, AI, and β) were used to identify early vascular alterations. Hepatorenal index (HRI) calculations served to quantify liver steatosis, while changes in subcutaneous and visceral fat thickness were used to quantify fat distribution. The given protocol was successfully completed by 28 volunteers. Long-term repeated CWI resulted in a significant decline in cIMT (p = 0.0001), AI (p = 0.0002), Beta (p = 0.0001), and PWV (p = 0.0001). PCSK9 (p = 0.01) and hsCRP (p = 0.01) showed a significant decrease when compared to initial values. In comparison to the starting values, liver fat accumulation decreased by 11% on average (HRI p = 0.001). LDL, TC, TG, and VLDL levels all significantly decreased as well. We suggest that repeated CWI may have beneficial impact on lipid, non-lipid, and lipid-related indices, as well as atherogenesis and liver fat storage. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a multifactorial disease of medium and large arteries, characterized by the presence of lipid-rich plaques lining the intima over time. It is the main cause of cardiovascular diseases and death worldwide. Redox imbalance and lipid peroxidation could play key roles in atherosclerosis by promoting a bundle of responses, including endothelial activation, inflammation, and foam cell formation. The oxidation of polyunsaturated fatty acids generates various lipid oxidation products such as reactive carbonyl species (RCS), including 4-hydroxy alkenals, malondialdehyde, and acrolein. RCS covalently bind to nucleophilic groups of nucleic acids, phospholipids, and proteins, modifying their structure and activity and leading to their progressive dysfunction. Protein lipoxidation is the non-enzymatic post-translational modification of proteins by RCS. Low-density lipoprotein (LDL) oxidation and apolipoprotein B (apoB) modification by RCS play a major role in foam cell formation. Moreover, oxidized LDLs are a source of RCS, which form adducts on a huge number of proteins, depending on oxidative stress intensity, the nature of targets, and the availability of detoxifying systems. Many systems are affected by lipoxidation, including extracellular matrix components, membranes, cytoplasmic and cytoskeletal proteins, transcription factors, and other components. The mechanisms involved in lipoxidation-induced vascular dysfunction are not fully elucidated. In this review, we focus on protein lipoxidation during atherogenesis. [ABSTRACT FROM AUTHOR]

Introduction: There is rising concern about vitamin D deficiency around the globe due to its increasing association with multiple medical disorders. Diabetes Mellitus (DM) is an established risk factor for atherosclerotic disorders, and Carotid Artery IntimaMedia Thickness (CIMT) is considered a radiological marker of subclinical atherosclerosis. Aim: To find a correlation between serum 25-hydroxy vitamin D (25-(OH)-D) levels and CIMT among patients with DM. Materials and Methods: A hospital-based cross-sectional study was conducted, including 100 adult patients with Type 2 DM who were admitted to the Department of Medicine at SCB Medical College and Hospital in Cuttack, Odisha, India from October 2020 to September 2021. Vitamin D deficiency was defined as serum 25-(OH)-D levels

Vascular endothelial cells are exposed to shear stresses with disturbed vs. laminar flow patterns, which lead to proinflammatory vs. antiinflammatory phenotypes, respectively. Effective treatment against endothelial inflammation and the consequent atherogenesis requires the identification of new therapeutic molecules and the development of drugs targeting these molecules. Using Connectivity Map, we have identified vitexin, a natural flavonoid, as a compound that evokes the gene-expression changes caused by pulsatile shear, which mimics laminar flow with a clear direction, vs. oscillatory shear (OS), which mimics disturbed flow without a clear direction. Treatment with vitexin suppressed the endothelial inflammation induced by OS or tumor necrosis factor-α. Administration of vitexin to mice subjected to carotid partial ligation blocked the disturbed flow-induced endothelial inflammation and neointimal formation. In hyperlipidemic mice, treatment with vitexin ameliorated atherosclerosis. Using SuperPred, we predicted that apurinic/apyrimidinic endonuclease1 (APEX1) may directly interact with vitexin, and we experimentally verified their physical interactions. OS induced APEX1 nuclear translocation, which was inhibited by vitexin. OS promoted the binding of acetyltransferase p300 to APEX1, leading to its acetylation and nuclear translocation. Functionally, knocking down APEX1 with siRNA reversed the OS-induced proinflammatory phenotype, suggesting that APEX1 promotes inflammation by orchestrating the NF-κB pathway. Animal experiments with the partial ligation model indicated that overexpression of APEX1 negated the action of vitexin against endothelial inflammation, and that endothelial-specific deletion of APEX1 ameliorated atherogenesis. We thus propose targeting APEX1 with vitexin as a potential therapeutic strategy to alleviate atherosclerosis.

Abstract Purpose Endothelial cell dysfunction is a major cause of early atherosclerosis. Although the role of extracellular vesicles in stabilizing atherosclerotic plaques is well established, the effect of circulating exosomes on plaque formation is still unknown. Here, we explored the effect of exosomes on atherosclerosis based on the function that exosomes can act on intercellular communication. Patients and methods We extracted serum exosomes from the blood of CHD patients (CHD-Exo) and healthy individuals (Con-Exo). The obtained exosomes were co-cultured with human umbilical vein endothelial cells (HUVECs) in vitro. In addition, we determined that circ_0001785 functions as a competing endogenous RNA (ceRNAs) in coronary artery disease by dual luciferase reporter gene analysis. The protective effect of circ_0001785 against endothelial cell injury was also verified using over-expression lentiviral transfection functional assays. In vivo experiments, we injected over-expressed circ_0001785 lentivirus into the tail vein of mice to observe its therapeutic effect on a mouse model of atherosclerosis. Results The vitro co-cultured results showed that the amount of plasma-derived exosomes have an increase in patients with coronary artery disease, and the inflammation and apoptosis of endothelial cells were exacerbated. Over-expression of circ_0001785 reduced endothelial cell injury through the ceRNA network pathway of miR-513a-5p/TGFBR3. Quantitative reverse transcription-polymerase chain reaction identified that the expressed amount of circ_0001785 was reduced in the circulating peripheral blood of CHD patients and increased within human and mouse atherosclerotic plaque tissue. The results of in vivo experiments showed that circ_0001785 reduced aortic endothelial cell injury and the formation of intraplaque neo-vascularization, and enhanced left ventricular diastolic function, thereby delaying the development of atherosclerosis in mice. Conclusion Our results demonstrated a new biomarker, exosome-derived circ_0001785, for atherogenesis, which can reduce endothelial cell injury and thus delay atherogenesis through the miR-513a-5p/TGFBR3 ceRNA network mechanism, providing an exosome-based intervention strategy for atherosclerosis.

The etiology of atherosclerosis is still unknown, but there are several hypotheses trying to explain this complex disease. Most consider atherosclerosis as a cholesterol storage disease. However, hypercholesterolemia is not a cause but a risk factor. Besides, like other well-known systemic risk factors, it does not explain the uneven distribution of atheromatous plaques in the vasculature. Atherosclerotic lesions develop mainly at vulnerable “risk points” of the arterial wall such as curvatures and near side branches, and predominantly in the left anterior descending (LAD), while the left circumflex (LCx) artery is relatively spared. Furthermore, atheromatous plaques are present mainly in the proximal segments in the LAD and LCx, in contrast to the right coronary artery (RCA), where plaques are more evenly distributed. The hemodynamic theory explains to some extent the distribution of atherosclerotic lesions and considers atherosclerosis as a reactive biological response of endothelial cells to wall shear stress. In this review, we discuss the interplay of concentration of low-density lipoproteins at the luminal surface and local hemodynamic forces (disturbed flow) that reduce wall shear stress in the process of plaque formation. Moreover, we present the distribution of atheromatous plaques in the coronary arteries in autopsy studies and imaging methods such as cardiac computed tomography angiography and invasive coronary angiography.

Coronary artery disease (CAD) remains the leading cause of mortality worldwide, driven primarily by atherogenesis. Recent efforts to understand sex differences in CAD have revealed distinct patterns in disease burden, risk factors, and clinical presentations. This review examines these sex differences in CAD, underscoring the importance of customized diagnostic and management strategies. Although men typically have higher rates of CAD prevalence and incidence, women face unique challenges, such as delayed diagnosis, atypical symptoms, and lower rates of medication prescription. Hormonal, genetic, and lifestyle factors all play a role in these disparities, with estrogen notably reducing CAD risk in women. Nontraditional risk factors, including chronic inflammation, psychological stress, socioeconomic status, and reproductive history, also contribute to CAD development and are often neglected in clinical settings. Addressing these differences requires increased awareness, more accurate diagnosis, and equitable healthcare access for both sexes. Furthermore, greater inclusion of women in CAD research is essential to better understand sex-specific mechanisms and optimize treatment outcomes. Personalizing CAD management based on sex-specific knowledge has the potential to improve prognosis and decrease disease incidence for both men and women.

Introduction: There is rising concern about vitamin D deficiency around the globe due to its increasing association with multiple medical disorders. Diabetes Mellitus (DM) is an established risk factor for atherosclerotic disorders, and Carotid Artery Intima- Media Thickness (CIMT) is considered a radiological marker of subclinical atherosclerosis. Aim: To find a correlation between serum 25-hydroxy vitamin D (25-(OH)-D) levels and CIMT among patients with DM. Materials and Methods: A hospital-based cross-sectional study was conducted, including 100 adult patients with Type 2 DM who were admitted to the Department of Medicine at SCB Medical College and Hospital in Cuttack, Odisha, India from October 2020 to September 2021. Vitamin D deficiency was defined as serum 25-(OH)-D levels <20 ng/mL, and insufficiency as <30 ng/mL. The demographic profile of patients, family history of Type 2 DM, smoking history, blood pressure, haemogram, blood sugar, serum electrolytes, and lipid profile were studied. CIMT of the bilateral Common Carotid Artery (CCA) was measured by B-mode ultrasonography. CIMT values ≥ 0.8 mm were considered abnormal. Data were analysed using appropriate statistical tests in Statistical Packages for Social Sciences (SPSS) version 26.0. Results: The present study included 55% males (n=55) and 45% females (n=45). The average age of the patients was 60 ±10 years, ranging from 26-75 years. Vitamin D deficiency was highly prevalent among patients with Type 2 DM (73% deficient, 12.5 ng/mL; 21% insufficient, 24.7 ng/mL). Vitamin D deficiency/ insufficiency was higher among male participants (57.5%, 62%) compared to females (42.4%, 38%). Vitamin D levels were significantly associated with dyslipidemia. Mean CIMT among the vitamin D deficiency versus insufficiency versus normal group were 0.87 versus 0.87 versus 0.7 mm on the right Common Carotid Artery (CCA), and 0.95 versus 0.86 versus 0.75 mm on the left CCA, respectively. Significant negative correlations were observed for HbA1c (r=-0.025), Triglycerides (r=-0.274), right CIMT (r=-0.284), and left CIMT (r=-0.264) with serum 25-(OH)-D levels. Conclusion: The majority of patients with Type 2 DM have concurrent vitamin D deficiency. A significant inverse linear association between serum vitamin D levels and CIMT was observed, indicating the association of vitamin D deficiency with subclinical atherosclerosis. Although unproven in the present study, the role of vitamin D supplementation in the improvement of atherosclerosis remains unclear. [ABSTRACT FROM AUTHOR]

Background and Objectives: The risk of developing cardiovascular diseases (CVD) in patients suffering from rheumatoid arthritis (RA) is two times higher compared to the general population. The objective of this retrospective study was to determine which cardiovascular complications can appear in men vs. women with rheumatoid arthritis. Early diagnosis and initiation of therapeutic measures to reduce the progression rate of rheumatoid arthritis, while also maintaining an active lifestyle, are the most important problems in young patients. Materials and Methods: We included a number of 200 patients, divided into two groups according to gender (124 women and 76 men) with rheumatoid arthritis, presenting various stages of disease concomitant with cardiovascular complications. We assessed traditional and non-traditional risk factors, as well as electrocardiographic and echocardiographic findings in both groups. Results: All patients presented an atherogenic coefficient over two, indicating a significant risk of atherogenesis. Men had elevated levels of total cholesterol compared with women (≥200 mg/dL; 77.6%—men vs. 25.8%—women, p < 0.001). The participants presented cardiac arrhythmias, especially in the active stage of RA. Women had an increased risk of atrial fibrillation by 2.308 times compared to men (p = 0.020). One of the most important complications found in young women was pulmonary arterial hypertension (p = 0.007). Conclusions: In daily clinical practice, the screening of RA is carried out in sufficiently. This disease is often undiagnosed, and the risk factors remain unassessed. As a result, RA patients continue to present an increased risk of developing CVD. [ABSTRACT FROM AUTHOR]

Abstract Background Thermoxidation of edible oil through deep fat frying results in the generation of several oxidized products that promote lipid peroxidation and ROS production when eaten. Consumption of thermoxidized oil in post-menopausal conditions where the estrogen level is low contributes to cardiovascular disease. This study evaluates the role of estradiol and antihyperlipidemic agents (AHD) in restoring the vascular health of ovariectomized (OVX) rats fed with thermoxidized palm oil (TPO) and thermoxidized soya oil (TSO) diets. Method A total of 10 groups of rats (n = 6) were set up for the experiment. Group I (normal control) rats were sham handled while other groups were OVX to bring about estrogen deficient post-menopausal state. Group II (OVX only) was not treated and received normal rat chow. Groups III-X were fed with either TPO or TSO diet for 12 weeks and treated with estradiol (ETD) 0.2 mg/kg/day, atorvastatin (ATV) 10 mg/kg/day, and a fixed-dose combination of ezetimibe and ATV (EZE 3 mg/kg/day + ATV 10 mg/kg/day). Results Pro-atherogenic lipids levels were significantly elevated in untreated TSO and TPO groups compared to OVX and sham, resulting in increased atherogenic and Coronary-risk indices. Treatment with Estradiol and AHDs significantly reduced the total cholesterol, triglycerides, low-density lipoprotein cholesterol as well as AI and CRI compared to untreated TSO and TPO groups, whereas TSO and TPO groups showed significant elevation in these parameters compared to Group I values. Moreover, aortic TNF-α levels were extremely elevated in the untreated TSO and TPO compared to Group I. TNF-α levels were significantly reduced in rats treated with AHDs and ETD. Localized oxidative stress was indicated in the aortic tissues of TSO and TPO-fed OVX rats by increased malondialdehyde and decreased glutathione, catalase, and superoxide dismutase levels. This contributed to a depletion in aortic nitric oxide. AHDs and ETD replenished the nitric oxide levels significantly. Histological evaluation of the aorta of TSO and TPO rats revealed increased peri-adventitia fat, aortic medial hypertrophy, and aortic recanalization. These pathologic changes were less seen in AHDs and ETD rats. Conclusion This study suggests that ETD and AHDs profoundly attenuate oxidized lipid-induced vascular inflammation and atherogenesis through oxidative-stress reduction and inhibition of TNF-α signaling.

Xu Cheng,1,2 Xinyan Chen,2,3 Min Zhang,3 Yufeng Wan,4 Shenglin Ge,1 Xiaowen Cheng2,3,5 1Department of Cardiovascular Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China; 2Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China; 3Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China; 4Department of Otolaryngology-Head Neck Surgery, the Affiliated Chaohu Hospital of Anhui Medical University, Hefei, Anhui, 238001, People’s Republic of China; 5Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of ChinaCorrespondence: Xiaowen Cheng, Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China, Email chengxiaowen@ahmu.edu.cn Shenglin Ge, Department of Cardiovascular Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China, Email geshenglin@ahmu.edu.cnAbstract: Atherosclerosis and its complications constitute some of the major diseases affecting humans worldwide. A core component of atherogenesis is endothelial cell damage and dysfunction, which also includes factors such as adhesion and proliferation of various cells. Multiple studies have shown that atherosclerosis and cancer share a common pathophysiological process and exhibit a degree of similarity. Sparcl-1 is a cysteine-rich secretory stromal cell protein present in the extracellular matrix and belongs to the Sparc family of proteins. Its role in tumor development has been widely investigated; however, its role in cardiovascular diseases has rarely been studied. Sparcl-1 is considered an oncogene correlated with the regulation of cell adhesion, migration, and proliferation and is also related to blood vessel integrity. In this review, the potential link between Sparcl-1 and atherosclerosis development is investigated, and recommendations on future research on the role of Sparcl-1 in atherogenesis are provided.Keywords: Sparcl-1, atherogenesis, cancer

The thymus represents a primary organ of the immune system, harboring the generation and maturation of T lymphocytes. Starting from childhood, the thymus undergoes involution, being replaced with adipose tissue, and by an advanced age nearly all the thymus parenchyma is represented by adipocytes. This decline of thymic function is associated with compromised maturation and selection of T lymphocytes, which may directly impact the development of inflammation and induce various autoinflammatory disorders, including atherosclerosis. For a long time, thymus health in adults has been ignored. The process of adipogenesis in thymus and impact of thymic fat on cardiometabolism remains a mysterious process, with many issues being still unresolved. Meanwhile, thymus functional activity has a potential to be regulated, since islets of thymopoeisis remain in adults even at an advanced age. The present review describes the intricate process of thymic adipose involution, focusing on the issues of the thymus’ role in the development of atherosclerosis and metabolic health, tightly interconnected with the state of vessels. We also review the recent information on the key molecular pathways and biologically active substances that may be targeted to manipulate both thymic function and atherosclerosis.

Plasminogen activator inhibitor-1 (PAI-1) has a significant role in fibrinolysis, atherogenesis, cellular senescence, and chronic inflammation. OSA (obstructive sleep apnea) leads to increased PAI-1 levels and the development of cardiovascular disease (CVD). The aim of this study was to determine the effects of CPAP therapy on coagulation parameters and PAI-1 in patients with severe OSA. This prospective, controlled study enrolled 57 patients who were newly diagnosed with severe OSA, 37 of whom had had good CPAP adherence after 6 months of therapy (usage of the device for at least 4 h per night), and their data were analyzed. The analysis showed a statistically significant increase in D-dimer values before CPAP therapy (415 (316.5–537.5)) vs. after therapy (499 (327–652)), p = 0.0282, and a decrease in fibrinogen values (3.665 ± 0.752 before CPAP therapy vs. 3.365 ± 0.771 after therapy, p = 0.0075)). PAI-1 concentration values before and after CPAP therapy did not differ significantly (17.35 ± 7.01 ng/mL before CPAP therapy vs. 17.42 ± 6.99 ng/mL after therapy, p = 0.9367). This study shows a tendency for fibrinolytic capacity to improve in patients with OSA after CPAP therapy, although PAI-1 levels did not differ significantly.

Plaque rupture and thrombosis are the most important clinical complications in the pathogenesis of stroke, coronary arteries, and peripheral vascular diseases. The identification of early biomarkers of plaque presence and susceptibility to ulceration could be of primary importance in preventing such life-threatening events. With the improvement of proteomic tools, large-scale technologies have been proven valuable in attempting to unravel pathways of atherosclerotic degeneration and identifying new circulating markers to be utilized either as early diagnostic traits or as targets for new drug therapies. To address these issues, different matrices of human origin, such as vascular cells, arterial tissues, plasma, and urine, have been investigated. Besides, proteomics was also applied to experimental atherosclerosis in order to unveil significant insights into the mechanisms influencing atherogenesis. This narrative review provides an overview of the last twenty years of omics applications to the study of atherogenesis and lesion vulnerability, with particular emphasis on lipoproteomics and vascular tissue proteomics. Major issues of tissue analyses, such as plaque complexity, sampling, availability, choice of proper controls, and lipoproteins purification, will be raised, and future directions will be addressed. [ABSTRACT FROM AUTHOR]

Purpose: Endothelial cell dysfunction is a major cause of early atherosclerosis. Although the role of extracellular vesicles in stabilizing atherosclerotic plaques is well established, the effect of circulating exosomes on plaque formation is still unknown. Here, we explored the effect of exosomes on atherosclerosis based on the function that exosomes can act on intercellular communication. Patients and methods: We extracted serum exosomes from the blood of CHD patients (CHD-Exo) and healthy individuals (Con-Exo). The obtained exosomes were co-cultured with human umbilical vein endothelial cells (HUVECs) in vitro. In addition, we determined that circ_0001785 functions as a competing endogenous RNA (ceRNAs) in coronary artery disease by dual luciferase reporter gene analysis. The protective effect of circ_0001785 against endothelial cell injury was also verified using over-expression lentiviral transfection functional assays. In vivo experiments, we injected over-expressed circ_0001785 lentivirus into the tail vein of mice to observe its therapeutic effect on a mouse model of atherosclerosis. Results: The vitro co-cultured results showed that the amount of plasma-derived exosomes have an increase in patients with coronary artery disease, and the inflammation and apoptosis of endothelial cells were exacerbated. Over-expression of circ_0001785 reduced endothelial cell injury through the ceRNA network pathway of miR-513a-5p/TGFBR3. Quantitative reverse transcription-polymerase chain reaction identified that the expressed amount of circ_0001785 was reduced in the circulating peripheral blood of CHD patients and increased within human and mouse atherosclerotic plaque tissue. The results of in vivo experiments showed that circ_0001785 reduced aortic endothelial cell injury and the formation of intraplaque neo-vascularization, and enhanced left ventricular diastolic function, thereby delaying the development of atherosclerosis in mice. Conclusion: Our results demonstrated a new biomarker, exosome-derived circ_0001785, for atherogenesis, which can reduce endothelial cell injury and thus delay atherogenesis through the miR-513a-5p/TGFBR3 ceRNA network mechanism, providing an exosome-based intervention strategy for atherosclerosis. [ABSTRACT FROM AUTHOR]

This study was designed to investigate the association between the perivascular fat attenuation index (FAI) and atherosclerotic plaque formation proximal to myocardial bridging (MB) of the left anterior descending artery (LAD) within 3 years. LAD-MB patients who underwent coronary computed tomography angiography at least twice between January 2016 and December 2022 were retrospectively included in this study. In total, 99 LAD-MB patients were included in the study. Based on the formation of atherosclerotic plaques proximal to LAD-MB during follow-up, the patients were classified into two groups: LAD-MB with plaque formation and LAD-MB without plaque formation within 3 years. The anatomical features, clinical factors, and proximal perivascular FAI of LAD-MB were measured and recorded. The association of the previously mentioned factors with the presence of atherosclerotic plaque proximal to LAD-MB was determined. The results showed that MB length, MB stenosis, and the perivascular FAI were significant predictors of the formation of atherosclerotic plaques proximal to LAD-MB. The area under the curve of the combined predictive model incorporating MB length, MB stenosis, and the perivascular FAI was 0.901(95% confidence interval: 0.824–0.952), with higher diagnostic performance than any other single parameter (all P < 0.05). Moreover, dynamic changes in the perivascular FAI of the vascular segments proximal to LAD-MB were higher in high-risk plaques than in non–high-risk plaques (P = 0.003). The combined use of the perivascular FAI, MB length, and MB stenosis may enable prediction of the probability of atherosclerotic plaque formation proximal to LAD-MB within 3 years. Dynamic changes in perivascular FAI were associated with the vulnerability of plaques proximal to LAD-MB. [ABSTRACT FROM AUTHOR]

Purpose of Review: The role of wnt signalling in atherogenesis raises the possibility that the wnt inhibitor, sclerostin, provides a natural defence to this process, and that anti-sclerostin antibodies might increase the risk of atherosclerosis and associated conditions such as CVD. This article aims to triangulate evidence concerning possible adverse effects of sclerostin inhibition on CVD risk. Recent Findings: Randomised controlled trials of treatment with the anti-sclerostin antibody, romosozumab, have yielded conflicting evidence with respect to possible adverse effects of sclerostin inhibition on CVD risk. To further examine the causal relationship between sclerostin inhibition and CVD risk, three Mendelian randomisation (MR) studies have examined effects of sclerostin lowering on CVD outcomes, using common genetic variants in the SOST gene which produces sclerostin, to mimic effects of a randomised trial. Concordant findings were seen in two studies, comprising an effect of sclerostin lowering on increased risk of MI and type II diabetes mellitus. One study also suggested that sclerostin lowering increases coronary artery calcification. Summary: Triangulation of evidence from different sources provides some suggestion that sclerostin lowering increases MI risk, supporting the need for CVD risk assessment when considering treatment with romosozumab. [ABSTRACT FROM AUTHOR]

The availability of sugar has expanded over the past 50 years, due to improved industrial processes and corn subsidies, particularly in the form of sweetened beverages. This correlates with a surge in the prevalence of cardiometabolic disorders, which has brought this issue back into the spotlight for public health. In this narrative review, we focus on the role of fructose in the genesis of cardiometabolic dyslipidemia (an increase in serum triglyceride-rich lipoproteins (TRL): VLDL, chylomicrons (CM), and their remnants) bringing together the most recent data on humans, which demonstrates the crucial interaction between glucose and fructose, increasing the synthesis while decreasing the catabolism of these particles in a synergistic downward spiral. After reviewing TRL metabolism, we discuss the fundamental principles governing the metabolism of fructose in the intestine and liver and the effects of dysregulated fructolysis, in conjunction with the activation of carbohydrate-responsive element-binding protein (ChREBP) by glucose and the resulting crosstalk. The first byproduct of fructose catabolism, fructose-1-P, is highlighted for its function as a signaling molecule that promotes fat synthesis. We emphasize the role of fructose/glucose interaction in the liver, which enhances de novo lipogenesis, triglyceride (TG) synthesis, and VLDL production. In addition, we draw attention to current research that demonstrates how fructose affects the activity of lipoprotein lipase by increasing the concentration of inhibitors such as apolipoprotein CIII (apoCIII) and angiopoietin-like protein 3 (ANGPTL3), which reduce the catabolism of VLDL and chylomicrons and cause the building up of their atherogenic remnants. The end outcome is a dual, synergistic, and harmful action that encourages atherogenesis. Thus, considering the growing concerns regarding the connection between sugar consumption and cardiometabolic disease, current research strongly supports the actions of public health organizations aimed at reducing sugar intake, including dietary guidance addressing "safe" limits for sugar consumption. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is the main risk factor for CVD and manifested by lipid accumulation, extracellular matrix protein deposition, and calcification in the intima and media of the large to medium size arteries promoting arterial stiffness and reduction of elasticity. It is initiated by endothelium activation and, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification), triggers the vessel narrowing and activation of inflammatory pathways. This review focuses on the different stages of AS development, ranging from endothelial dysfunction to plaque rupture and the role of genetic abnormalities in AS development. In addition, the correlation of monocyte recruitment and atherogenesis, cytokine involvement with the role of phagocytosis in AS, fundamental signaling pathways in multiple stages of AS, and genetics of AS and the molecular mechanisms of plaque rupture and cap formation are covered here to provide a global view of the disease. [ABSTRACT FROM AUTHOR]

Carotid atherosclerosis is a significant cause of cerebrovascular disease. However, with many candidate markers, precise assessment of its development and progression risks is still limited. This paper reviews state-of-the-art concepts of microRNA as an atherogenesis biomarker throughout various stages including endothelial dysfunction, cholesterol/lipid metabolism, inflammation, oxidative stress, angiogenesis regulation, and proliferation and migration of vascular smooth muscle cells. Based on the available literature, we have described most significant microRNAs for each stage characterized in brief. We have visualized interactions between microRNAs and validated target genes with MIENTURNET and suggest and justify a set of microRNAs for further pilot studies of carotid atherosclerosis.

Background: Obesity and being overweight elevate triglycerides, blood cholesterol, blood pressure, and LDL levels while decreasing HDL levels. This study aimed to examine the impact of eight weeks of interval training combined with melatonin consumption on novel obesity indicators and the atherogenic index in overweight and obese women.Methods: This semi-experimental, applied research involved 40 women aged between 30 to 45 years. They were randomly divided into four groups of ten each: intense interval training plus melatonin consumption (Group I), intense interval training plus placebo (Group II), melatonin consumption only (Group III), and a control group. The high-intensity interval training was conducted over eight weeks, with three sessions weekly. The regimen progressed from 5 repetitions in the first and second weeks to 6 in the third and fourth weeks, 7 in the fifth and sixth weeks, and 8 in the final two weeks. Groups I and III consumed 3 mg of melatonin tablets (manufactured by Razak company, Iran) nightly, an hour before bedtime, for the study duration. Data were analyzed using SPSS version 22 at 0.05 significance level.Results: The combination of eight weeks of interval training and melatonin consumption significantly impacted the visceral adiposity index (VAI), atherogenic plasma index (AIP), TC/HDL-c ratio, and HDL-c levels in overweight and obese women (P=0.001 for each). However, there were no significant effects on the ApoA-1/ApoB ratio, body adiposity index (BAI), or ApoA- 1 and Apo B levels (P=0.089, P=0.053, P=0.696, P=0.156, respectively).Conclusion: Intensive interval training coupled with melatonin supplementation positively influences obesity management, weight control, and cardiovascular disease risk reduction in overweight and obese women.

Background: Thermoxidation of edible oil through deep fat frying results in the generation of several oxidized products that promote lipid peroxidation and ROS production when eaten. Consumption of thermoxidized oil in post-menopausal conditions where the estrogen level is low contributes to cardiovascular disease. This study evaluates the role of estradiol and antihyperlipidemic agents (AHD) in restoring the vascular health of ovariectomized (OVX) rats fed with thermoxidized palm oil (TPO) and thermoxidized soya oil (TSO) diets. Method: A total of 10 groups of rats (n = 6) were set up for the experiment. Group I (normal control) rats were sham handled while other groups were OVX to bring about estrogen deficient post-menopausal state. Group II (OVX only) was not treated and received normal rat chow. Groups III-X were fed with either TPO or TSO diet for 12 weeks and treated with estradiol (ETD) 0.2 mg/kg/day, atorvastatin (ATV) 10 mg/kg/day, and a fixed-dose combination of ezetimibe and ATV (EZE 3 mg/kg/day + ATV 10 mg/kg/day). Results: Pro-atherogenic lipids levels were significantly elevated in untreated TSO and TPO groups compared to OVX and sham, resulting in increased atherogenic and Coronary-risk indices. Treatment with Estradiol and AHDs significantly reduced the total cholesterol, triglycerides, low-density lipoprotein cholesterol as well as AI and CRI compared to untreated TSO and TPO groups, whereas TSO and TPO groups showed significant elevation in these parameters compared to Group I values. Moreover, aortic TNF-α levels were extremely elevated in the untreated TSO and TPO compared to Group I. TNF-α levels were significantly reduced in rats treated with AHDs and ETD. Localized oxidative stress was indicated in the aortic tissues of TSO and TPO-fed OVX rats by increased malondialdehyde and decreased glutathione, catalase, and superoxide dismutase levels. This contributed to a depletion in aortic nitric oxide. AHDs and ETD replenished the nitric oxide levels significantly. Histological evaluation of the aorta of TSO and TPO rats revealed increased peri-adventitia fat, aortic medial hypertrophy, and aortic recanalization. These pathologic changes were less seen in AHDs and ETD rats. Conclusion: This study suggests that ETD and AHDs profoundly attenuate oxidized lipid-induced vascular inflammation and atherogenesis through oxidative-stress reduction and inhibition of TNF-α signaling. [ABSTRACT FROM AUTHOR]

Tissue inhibitor of metalloproteinases-1 (TIMP-1), an important regulator of matrix metalloproteinases (MMPs), has recently been shown to interact with CD74, a receptor for macrophage migration inhibitory factor (MIF). However, the biological effects mediated by TIMP-1 through CD74 remain largely unexplored. Using sequence alignment and in silico protein–protein docking analysis, we demonstrated that TIMP-1 shares residues with both MIF and MIF-2, crucial for CD74 binding, but not for CXCR4. Subcellular colocalization, immunoprecipitation, and internalization experiments supported these findings, demonstrating that TIMP-1 interacts with surface-expressed CD74, resulting in its internalization in a dose-dependent manner, as well as with a soluble CD74 ectodomain fragment (sCD74). This prompted us to study the effects of the TIMP-1–CD74 axis on monocytes and vascular smooth muscle cells (VSCMs) to assess its impact on vascular inflammation. A phospho-kinase array revealed the activation of serine/threonine kinases by TIMP-1 in THP-1 pre-monocytes, in particular AKT. Similarly, TIMP-1 dose-dependently triggered the phosphorylation of AKT and ERK1/2 in primary human monocytes. Importantly, Transwell migration, 3D-based Chemotaxis, and flow adhesion assays demonstrated that TIMP-1 engagement of CD74 strongly promotes the recruitment response of primary human monocytes, while live cell imaging studies revealed a profound activating effect on VSMC proliferation. Finally, re-analysis of scRNA-seq data highlighted the expression patterns of TIMP-1 and CD74 in human atherosclerotic lesions, thus, together with our experimental data, indicating a role for the TIMP-1–CD74 axis in vascular inflammation and atherosclerosis. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinemia (HHcy) worsens cardiovascular outcomes by impairing vascular function and promoting chronic inflammation via release of danger-associated molecular patterns, such as high-mobility group box-1 (HMGB-1). Elevated levels of HMGB-1 have recently been reported in patients with HHcy. Therefore, targeting HMGB-1 may be a potential therapy to improve HHcy-induced cardiovascular pathologies. This study aimed to further elucidate HMGB-1′s role during acute HHcy and HHcy-induced atherogenesis and to determine if inhibiting HMGB-1 with glycyrrhizic acid (Glyz) improved vascular function. Male New Zealand White rabbits (n = 25) were placed on either a standard control chow (CD; n = 15) or atherogenic diet (AD; n = 10) for 4 weeks. Rabbit serum and Krebs taken from organ bath studies were collected to quantify HMGB-1 levels. Isometric tension analysis was performed on abdominal aorta (AA) rings from CD and AD rabbits. Rings were incubated with homocysteine (Hcy) [3 mM] for 60 min to induce acute HHcy or rhHMGB-1 [100 nM]. Vascular function was assessed by relaxation to cumulative doses of acetylcholine. Markers of vascular dysfunction and inflammation were quantified in the endothelium, media, and adventitia of AA rings. HMGB-1 was significantly upregulated in serum (p < 0.0001) and Krebs (p < 0.0001) after Hcy exposure or an AD. Incubation with Hcy (p < 0.0001) or rhHMGB-1 (p < 0.0001) and an AD (p < 0.0001) significantly reduced relaxation to acetylcholine, which was markedly improved by Glyz. HMGB-1 expression was elevated (p < 0.0001) after Hcy exposure and AD (p < 0.0001) and was normalized after Glyz treatment. Moreover, markers of vascular function, cell stress and inflammation were also reduced after Glyz. These results demonstrate that HMGB-1 has a central role during HHcy-induced vascular dysfunction and inhibiting it with Glyz could be a potential treatment option for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The residual risk for arteriosclerotic cardiovascular disease after optimal statin treatment may amount to 50% and is the consequence of both immunological and lipid disturbances. Regarding the lipid disturbances, the role of triglyceride-rich lipoproteins (TRLs) and their remnants has come to the forefront in the past decade. Triglycerides (TGs) stand as markers of the remnants of the catabolism of TRLs that tend to contain twice as much cholesterol as compared to LDL. The accumulation of circulating TRLs and their partially lipolyzed derivatives, known as "remnants", is caused mainly by ineffective triglyceride catabolism. These cholesterol-enriched remnant particles are hypothesized to contribute to atherogenesis. The aim of the present narrative review is to briefly summarize the main pathways of TRL metabolism, bringing to the forefront the newly discovered role of apolipoproteins, the key physiological function of lipoprotein lipase and its main regulators, the importance of the fluxes of these particles in the post-prandial period, their catabolic rates and the role of apo CIII and angiopoietin-like proteins in the partition of TRLs during the fast-fed cycle. Finally, we provide a succinct summary of the new and old therapeutic armamentarium and the outcomes of key current trials with a final outlook on the different methodological approaches to measuring TRL remnants, still in search of the gold standard. [ABSTRACT FROM AUTHOR]

The etiology of atherosclerosis is still unknown, but there are several hypotheses trying to explain this complex disease. Most consider atherosclerosis as a cholesterol storage disease. However, hypercholesterolemia is not a cause but a risk factor. Besides, like other well-known systemic risk factors, it does not explain the uneven distribution of atheromatous plaques in the vasculature. Atherosclerotic lesions develop mainly at vulnerable "risk points" of the arterial wall such as curvatures and near side branches, and predominantly in the left anterior descending (LAD), while the left circumflex (LCx) artery is relatively spared. Furthermore, atheromatous plaques are present mainly in the proximal segments in the LAD and LCx, in contrast to the right coronary artery (RCA), where plaques are more evenly distributed. The hemodynamic theory explains to some extent the distribution of atherosclerotic lesions and considers atherosclerosis as a reactive biological response of endothelial cells to wall shear stress. In this review, we discuss the interplay of concentration of low-density lipoproteins at the luminal surface and local hemodynamic forces (disturbed flow) that reduce wall shear stress in the process of plaque formation. Moreover, we present the distribution of atheromatous plaques in the coronary arteries in autopsy studies and imaging methods such as cardiac computed tomography angiography and invasive coronary angiography. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a systemic disease in which focal lesions in arteries promote the build-up of lipoproteins and cholesterol they are transporting. The development of atheroma (atherogenesis) narrows blood vessels, reduces the blood supply and leads to cardiovascular diseases. According to the World Health Organization (WHO), cardiovascular diseases are the leading cause of death, which has been especially boosted since the COVID-19 pandemic. There is a variety of contributors to atherosclerosis, including lifestyle factors and genetic predisposition. Antioxidant diets and recreational exercises act as atheroprotectors and can retard atherogenesis. The search for molecular markers of atherogenesis and atheroprotection for predictive, preventive and personalized medicine appears to be the most promising direction for the study of atherosclerosis. In this work, we have analyzed 1068 human genes associated with atherogenesis, atherosclerosis and atheroprotection. The hub genes regulating these processes have been found to be the most ancient. In silico analysis of all 5112 SNPs in their promoters has revealed 330 candidate SNP markers, which statistically significantly change the affinity of the TATA-binding protein (TBP) for these promoters. These molecular markers have made us confident that natural selection acts against underexpression of the hub genes for atherogenesis, atherosclerosis and atheroprotection. At the same time, upregulation of the one for atheroprotection promotes human health. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) play a critical role in the regulation of atherosclerosis. Here, we investigated the role of the lncRNA growth arrest-specific 5 (lncR-GAS5) in atherogenesis. We found that the enforced expression of lncR-GAS5 contributed to the development of atherosclerosis, which presented as increased plaque size and reduced collagen content. Moreover, impaired autophagy was observed, as shown by a decreased LC3II/LC3I protein ratio and an elevated P62 level in lncR-GAS5-overexpressing human aortic endothelial cells. By contrast, lncR-GAS5 knockdown promoted autophagy. Moreover, serine/arginine-rich splicing factor 10 (SRSF10) knockdown increased the LC3II/LC3I ratio and decreased the P62 level, thus enhancing the formation of autophagic vacuoles, autolysosomes, and autophagosomes. Mechanistically, lncR-GAS5 regulated the downstream splicing factor SRSF10 to impair autophagy in the endothelium, which was reversed by the knockdown of SRSF10. Further results revealed that overexpression of the lncR-GAS5-targeted gene miR-193-5p promoted autophagy and autophagic vacuole accumulation by repressing its direct target gene, SRSF10. Notably, miR-193-5p overexpression decreased plaque size and increased collagen content. Altogether, these findings demonstrate that lncR-GAS5 partially contributes to atherogenesis and plaque instability by impairing endothelial autophagy. In conclusion, lncR-GAS5 overexpression arrested endothelial autophagy through the miR-193-5p/SRSF10 signaling pathway. Thus, miR-193-5p/SRSF10 may serve as a novel treatment target for atherosclerosis. [ABSTRACT FROM AUTHOR]

Remodeling of extracellular matrix proteins underlies the development of cardiovascular disease. Herein, we utilized a novel molecular probe, collagen hybridizing peptide (CHP), to target collagen molecular damage during atherogenesis. The thoracic aorta was dissected from ApoE−/− mice that had been on a high-fat diet for 0–18 weeks. Using an optimized protocol, tissues were stained with Cy3-CHP and digested to quantify CHP with a microplate assay. Results demonstrated collagen molecular damage, inferred from Cy3-CHP fluorescence, was a function of location and time on the high-fat diet. Tissue from the aortic arch showed a significant increase in collagen molecular damage after 18 weeks, while no change was observed in tissue from the descending aorta. No spatial differences in fluorescence were observed between the superior and inferior arch tissue. Our results provide insight into the early changes in collagen during atherogenesis and present a new opportunity in the subclinical diagnosis of atherosclerosis. [ABSTRACT FROM AUTHOR]