The role of metabolic disorders in the development of atherosclerosis.

Atherosclerosis is a major risk factor for cardiovascular disease (CVD), which is the leading cause of death worldwide. Atherosclerosis is initiated by endothelial activation, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification) triggering vasoconstriction and activation of inflammatory pathways. This review focuses on the various stages in the development of atherosclerosis, ranging from endothelial dysfunction to plaque rupture. In addition, disorders of lipid, glucose and amino acid metabolism in atherosclerosis are considered here. The key pathological stages of metabolism disruption and their role in atherosclerosis are considered in detail which may be helpful for the more better understanding of atherosclerosis pathogenesis. Finally, some therapeutic approaches aimed at modulating lipid metabolism will also be presented which show the therapeutic targets (enzymes and transport proteins) which modulation can prevent further deterioration of patients symptoms.

LncRNAs Are Key Regulators of Transcription Factor-Mediated Endothelial Stress Responses.

The functional role of long noncoding RNAs in the endothelium is highly diverse. Among their many functions, regulation of transcription factor activity and abundance is one of the most relevant. This review summarizes the recent progress in the research on the lncRNA-transcription factor axes and their implications for the vascular endothelium under physiological and pathological conditions. The focus is on transcription factors critical for the endothelial response to external stressors, such as hypoxia, inflammation, and shear stress, and their lncRNA interactors. These regulatory interactions will be exemplified by a selected number of lncRNAs that have been identified in the endothelium under physiological and pathological conditions that are influencing the activity or protein stability of important transcription factors. Thus, lncRNAs can add a layer of cell type-specific function to transcription factors. Understanding the interaction of lncRNAs with transcription factors will contribute to elucidating cardiovascular disease pathologies and the development of novel therapeutic approaches.

Towards Targeting Endothelial Rap1B to Overcome Vascular Immunosuppression in Cancer.

The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression-a state where ECs resist cytotoxic CD8+ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness is significantly reduced by tumor EC anergy. Anti-angiogenic treatments aim to normalize tumor vessels and improve immune cell infiltration. Despite their potential, these therapies often cause significant systemic toxicities, necessitating new treatments. The small GTPase Rap1B emerges as a critical regulator of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific Rap1B knockout mice show that the absence of Rap1B impairs tumor growth, alters vessel morphology, and increases CD8+ T cell infiltration and activation. This indicates that Rap1B mediates VEGF-A's immunosuppressive effects, making it a promising target for overcoming vascular immunosuppression in cancer. Rap1B shares structural and functional similarities with RAS oncogenes. We propose that targeting Rap1B could enhance therapies' efficacy while minimizing adverse effects by reversing endothelial anergy. We briefly discuss strategies successfully developed for targeting RAS as a model for developing anti-Rap1 therapies.

EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake.

BACKGROUND: Atherosclerotic plaques form unevenly due to disturbed blood flow, causing localized endothelial cell (EC) dysfunction. Obesity exacerbates this process, but the underlying molecular mechanisms are unclear. The transcription factor EPAS1 (HIF2A) has regulatory roles in endothelium, but its involvement in atherosclerosis remains unexplored. This study investigates the potential interplay between EPAS1, obesity, and atherosclerosis. METHODS: Responses to shear stress were analyzed using cultured porcine aortic EC exposed to flow in vitro coupled with metabolic and molecular analyses and by en face immunostaining of murine aortic EC exposed to disturbed flow in vivo. Obesity and dyslipidemia were induced in mice via exposure to a high-fat diet or through Leptin gene deletion. The role of Epas1 in atherosclerosis was evaluated by inducible endothelial Epas1 deletion, followed by hypercholesterolemia induction (adeno-associated virus-PCSK9 [proprotein convertase subtilisin/kexin type 9]; high-fat diet). RESULTS: En face staining revealed EPAS1 enrichment at sites of disturbed blood flow that are prone to atherosclerosis initiation. Obese mice exhibited substantial reduction in endothelial EPAS1 expression. Sulforaphane, a compound with known atheroprotective effects, restored EPAS1 expression and concurrently reduced plasma triglyceride levels in obese mice. Consistently, triglyceride derivatives (free fatty acids) suppressed EPAS1 in cultured EC by upregulating the negative regulator PHD2. Clinical observations revealed that reduced serum EPAS1 correlated with increased endothelial PHD2 and PHD3 in obese individuals. Functionally, endothelial EPAS1 deletion increased lesion formation in hypercholesterolemic mice, indicating an atheroprotective function. Mechanistic insights revealed that EPAS1 protects arteries by maintaining endothelial proliferation by positively regulating the expression of the fatty acid-handling molecules CD36 (cluster of differentiation 36) and LIPG (endothelial type lipase G) to increase fatty acid beta-oxidation. CONCLUSIONS: Endothelial EPAS1 attenuates atherosclerosis at sites of disturbed flow by maintaining EC proliferation via fatty acid uptake and metabolism. This endothelial repair pathway is inhibited in obesity, suggesting a novel triglyceride-PHD2 modulation pathway suppressing EPAS1 expression. These findings have implications for therapeutic strategies addressing vascular dysfunction in obesity.

Effect of endothelium on the anticoagulant activity of a covalent antithrombin-heparin complex.

We developed a covalent antithrombin-heparin complex (ATH) with superior In vivo anticoagulant efficacy compared to non-covalent antithrombin (AT) + unfractionated heparin (H). Previous in vitro studies of ATH, investigating the mechanisms behind its efficacy, were done in the absence of endothelium. Since the endothelial surface modulates hemostasis, we investigated its impact on the in vitro anticoagulant properties of ATH and AT+H. Discontinuous second order rate constant enzyme inhibition assays, fibrin formation, and plasma clot generation were performed in the presence of ATH or AT+H, with and without endothelium present. ATH had an increased rate of direct inhibition of IIa and Xa, and increased inhibition of IIa-induced fibrin formation, compared to AT+H. When compared at equal anti-Xa levels, ATH was less effective than AT+H at catalyzing inhibition of plasma clot generation. These results were found in both the presence and absence of endothelium. Endothelium decreased the rate of IIa inhibition, and reduced clot time in IIa-induced fibrin formation and plasma clot generation assays, for both ATH and AT+H. Endothelium did not impact the activity of ATH differently to AT+H. This supports the growing body of evidence suggesting ATH may be a beneficial anticoagulant for potential clinical use.

Anti TNF-Alpha Treatment Improves Microvascular Endothelial Dysfunction in Rheumatoid Arthritis Patients.

Nailfold capillaroscopy is a non-invasive investigation, which allows for the study of the microvasculature (anatomical and functional). Rheumatoid arthritis (RA) is associated with a high risk of cardiovascular atherosclerotic diseases, with endothelial dysfunction (macrovascular and microvascular) representing the first step in atherosclerosis development. The aim of this study is represented by the assessment of microvascular endothelial dysfunction in RA patients by means of nailfold capillaroscopy and to assess its evolution after a period of 12 months of anti TNF-alpha treatment. The study included 70 consecutive patients with RA and 70 healthy subjects, matched for age and gender, as the control group. Rheumatoid factor, anti-cyclic citrullinated peptide antibodies, serum TNF-α, C reactive protein, and erythrocytes sedimentation rate were evaluated in all patients, but in controls, only rheumatoid factor, serum TNF-α, C reactive protein, and erythrocytes sedimentation rate were measured. The RA activity was measured by DAS28. Nailfold capillaroscopy was carried out in all patients and controls, determining the baseline nailfold capillary density (Db), nailfold capillary density during reactive hyperemia (Dh), and nailfold capillary density after venous congestion (Dc). Data were presented as mean ± standard deviation. Statistical analysis was performed using ANOVA and Pearson's correlation, with p < 0.05 being statistically significant. Db, Dh, and Dc were lower in RA patients than in controls (p < 0.0001), correlating with RA activity and TNF-α (p < 0.05). After 12 months of anti TNF-α treatment, microvascular endothelial dysfunction improved (p < 0.0001). Microvascular endothelial dysfunction can be assessed by nailfold capillaroscopy, with anti TNF-α medication contributing to its improvement.

Crucial Interactions between Altered Plasma Trace Elements and Fatty Acids Unbalance Ratio to Management of Systemic Arterial Hypertension in Diabetic Patients: Focus on Endothelial Dysfunction.

The coexistence of SAH with T2DM is a common comorbidity. In this study, we investigated the link between altered plasma antioxidant trace elements (ATE: manganese, selenium, zinc, and copper) and fatty acids ratio (FAR: polyunsaturated/saturated) imbalance as transition biomarkers between vascular pathology (SAH) to metabolic pathology (T2DM). Our data revealed strong correlation between plasma ATE and FAR profile, which is modified during SAH-T2DM association compared to the healthy group. This relationship is mediated by lipotoxicity (simultaneously prominent visceral adipose tissue lipolysis, significant flow of non-esterified free fatty acids release, TG-Chol-dyslipidemia, high association of total SFA, palmitic acid, arachidonic acid, and PUFA ω6/PUFA ω3; drop in tandem of PUFA/SFA and EPA + DHA); oxidative stress (lipid peroxidation confirmed by TAS depletion and MDA rise, concurrent drop of Zn/Cu-SOD, GPx, GSH, Se, Zn, Se/Mn, Zn/Cu; concomitant enhancement of Cu, Mn, and Fe); endothelial dysfunction (endotheline-1 increase); athero-thrombogenesis risk (concomitant rise of ApoB100/ApoA1, Ox-LDL, tHcy, and Lp(a)), and inflammation (higher of Hs-CRP, fibrinogen and ferritin). Our study opens to new therapeutic targets and to better dietary management, such as to establishing dietary ATE and PUFA ω6/PUFA ω3 or PUFA/SFA reference values for atherosclerotic risk prevention in hypertensive/diabetic patients.

Licorice Extract Isoliquiritigenin Protects Endothelial Function in Type 2 Diabetic Mice.

Endothelial dysfunction occurs prior to atherosclerosis, which is an independent predictor of cardiovascular diseases (CVDs). Diabetes mellitus impairs endothelial function by triggering oxidative stress and inflammation in vascular tissues. Isoliquiritigenin (ISL), one of the major bioactive ingredients extracted from licorice, has been reported to inhibit inflammation and oxidative stress. However, the therapeutic effects of ISL on ameliorating type 2 diabetes (T2D)-associated endothelial dysfunction remain unknown. In our animal study, db/db male mice were utilized as a model for T2D-associated endothelial dysfunction, while their counterpart, heterozygote db/m+ male mice, served as the control. Mouse brain microvascular endothelial cells (mBMECs) were used for in vitro experiments. Interleukin-1ß (IL-1ß) was used to induce endothelial cell dysfunction. ISL significantly reversed the impairment of endothelium-dependent relaxations (EDRs) in db/db mouse aortas. ISL treatment decreased ROS (reactive oxygen species) levels in db/db mice aortic sections and IL-1ß-treated endothelial cells. Encouragingly, ISL attenuated the overexpression of pro-inflammatory factors MCP-1, TNF-α, and IL-6 in db/db mouse aortas and IL-1ß-impaired endothelial cells. The NOX2 (NADPH oxidase 2) overexpression was inhibited by ISL treatment. Notably, ISL treatment restored the expression levels of IL-10, SOD1, Nrf2, and HO-1 in db/db mouse aortas and IL-1ß-impaired endothelial cells. This study illustrates, for the first time, that ISL attenuates endothelial dysfunction in T2D mice, offering new insights into the pharmacological effects of ISL. Our findings demonstrate the potential of ISL as a promising therapeutic agent for the treatment of vascular diseases, paving the way for the further exploration of novel vascular therapies.

Effect of Spermidine on Endothelial Function in Systemic Lupus Erythematosus Mice.

Endothelial dysfunction is common in Systemic Lupus Erythematosus (SLE), even in the absence of cardiovascular disease. Evidence suggests that impaired mitophagy contributes to SLE. Mitochondrial dysfunction is also associated with impaired endothelial function. Spermidine, a natural polyamine, stimulates mitophagy by the PINK1-parkin pathway and counters age-associated endothelial dysfunction. However, the effect of spermidine on mitophagy and vascular function in SLE has not been explored. To address this gap, 9-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned to spermidine treatment (lpr_Spermidine and MpJ_Spermidine) for 8 weeks or as control (lpr_Control and MpJ_Control). lpr_Control mice exhibited impaired endothelial function (e.g., decreased relaxation to acetylcholine), increased markers of inflammation, and lower protein content of parkin, a mitophagy marker, in the thoracic aorta. Spermidine treatment prevented endothelial dysfunction in MRL-lpr mice. Furthermore, aortas from lpr_Spermidine mice had lower levels of inflammatory markers and higher levels of parkin. Lupus phenotypes were not affected by spermidine. Collectively, these results demonstrate the beneficial effects of spermidine treatment on endothelial function, inflammation, and mitophagy in SLE mice. These results support future studies of the beneficial effects of spermidine on endothelial dysfunction and cardiovascular disease risk in SLE.

Gestational influenza A virus infection elicits nonresolving vascular dysfunction and T-cell accumulation in the aorta of mice.

T-cell accumulation within the aorta promotes endothelial dysfunction and the genesis of cardiovascular disease, including hypertension and atherosclerosis. Viral infection during pregnancy is also known to mediate marked acute endothelial dysfunction, but it is not clear whether T cells are recruited to the aorta and whether the dysfunction persists postpartum. Here, we demonstrate that influenza A virus (IAV) infection during pregnancy in a murine model resulted in endothelial dysfunction of the aorta, which persisted for up to 60 days postinfection and was associated with higher levels of IFN-γ mRNA expression within the tissue. In the absence of infection, low numbers of naïve CD4+ and CD8+ T cells, central memory T cells, and effector memory T cells were observed in the aorta. However, with IAV infection, these T-cell subsets were significantly increased with a notable accumulation of IAV-specific CD8+ effector memory T cells. Critically, this increase was maintained out to at least 60 days. In contrast, IAV infection in nonpregnant female mice resulted in modest endothelial dysfunction with no accumulation of T cells within the aorta. These data, therefore, demonstrate that the aorta is a site of T-cell recruitment and retention after IAV infection during pregnancy. Although IAV-specific memory T cells could theoretically confer protection against future influenza infection, nonspecific memory T-cell activation and IFN-γ production in the aorta could also contribute to future endothelial dysfunction and cardiovascular disease.NEW & NOTEWORTHY Pregnancy is a risk factor for cardiovascular complications to influenza A virus (IAV) infection. We demonstrate that gestational IAV infection caused endothelial dysfunction of the maternal aorta, which persisted for 60 days postinfection in mice. Various T cells accumulated within the aorta at 60 days because of the infection, and this was associated with elevated levels of the proinflammatory cytokine, IFN-γ. Our study demonstrates a novel "long influenza" cardiovascular phenotype in female mice.

Lipotoxicity-Related Hematological Disorders in Obesity.

Lipotoxicity can mediate endothelial dysfunction in obesity. Altered endothelial cell phenotype during the pathobiological course of the lipotoxicity may lead to hemostatic abnormalities, which is a hallmark of several hematological disorders. Impaired hemostasis could also be directly related to numerous metabolic diseases such as hypertension, diabetes, and atherosclerosis. On the other hand, the local hematopoietic bone marrow (BM) renin-angiotensin system (RAS) contributes to the development of atherosclerosis via acting on the lipotoxicity processes. Local BM RAS, principally an autocrine/paracrine/intracrine hematological system, is located at the crossroads of cellular regulation, molecular interactions, and lipotoxicity-mediated vascular endothelial dysfunction. The positive regulatory role of plasma LDL on AT1 receptor-mediated hematopoietic stem cell (HSC) differentiation and the production of pro-atherogenic monocytes have been described. LDL-regulated HSC function may explain in part hypercholesterolemia-induced inflammation as well as the anti-inflammatory and anti-atherosclerotic effects of AT1 receptor blockers. The role of local adipose tissue RAS is directly related to the pathogenesis of metabolic derangements in obesity. There may be a crosstalk between local BM RAS and local adipose tissue RAS at the genomics and transcriptomics levels. This chapter aims to review hematological alterations propagating the pathological influences of lipotoxicity on the vascular endothelium.

Endothelial Dysfunction in Obesity and Therapeutic Targets.

Parallel to the increasing prevalence of obesity in the world, the mortality from cardiovascular disease has also increased. Low-grade chronic inflammation in obesity disrupts vascular homeostasis, and the dysregulation of adipocyte-derived endocrine and paracrine effects contributes to endothelial dysfunction. Besides the adipose tissue inflammation, decreased nitric oxide (NO)-bioavailability, insulin resistance (IR), and oxidized low-density lipoproteins (oxLDLs) are the main factors contributing to endothelial dysfunction in obesity and the development of cardiorenal metabolic syndrome. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in the profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Higher stiffness parameter ß, increased oxidative stress, upregulation of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADP) oxidase in PVAT turn the macrophages into pro-atherogenic phenotypes by oxLDL-induced adipocyte-derived exosome-macrophage crosstalk and contribute to the endothelial dysfunction. In clinical practice, carotid ultrasound, higher leptin levels correlate with irisin over-secretion by human visceral and subcutaneous adipose tissues, and remnant cholesterol (RC) levels predict atherosclerotic disease in obesity. As a novel therapeutic strategy for cardiovascular protection, liraglutide improves vascular dysfunction by modulating a cyclic adenosine monophosphate (cAMP)-independent protein kinase A (PKA)-AMP-activated protein kinase (AMPK) pathway in PVAT in obese individuals. Because the renin-angiotensin-aldosterone system (RAAS) activity, hyperinsulinemia, and the resultant IR play key roles in the progression of cardiovascular disease in obesity, RAAS-targeted therapies contribute to improving endothelial dysfunction. By contrast, arginase reciprocally inhibits NO formation and promotes oxidative stress. Thus, targeting arginase activity as a key mediator in endothelial dysfunction has therapeutic potential in obesity-related vascular comorbidities. Obesity-related endothelial dysfunction plays a pivotal role in the progression of type 2 diabetes (T2D). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (thiazolidinedione), is a popular drug for treating diabetes; however, it leads to increased cardiovascular risk. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) significantly improves endothelial dysfunction and mortality occurring through redox-dependent mechanisms. Although endothelial dysfunction and oxidative stress are alleviated by either metformin or EMPA, currently used drugs to treat obesity-related diabetes neither possess the same anti-inflammatory potential nor simultaneously target endothelial cell dysfunction and obesity equally. While therapeutic interventions with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide or bariatric surgery reverse regenerative cell exhaustion, support vascular repair mechanisms, and improve cardiometabolic risk in individuals with T2D and obesity, the GLP-1 analog exendin-4 attenuates endothelial endoplasmic reticulum stress.

Phosphorylated vimentin-triggered fibronectin matrix disaggregation enhances the dissemination of Treponema pallidum subsp. pallidum across the microvascular endothelial barrier.

Fibronectin (FN) is an essential component of the extracellular matrix (ECM) that protects the integrity of the microvascular endothelial barrier (MEB). However, Treponema pallidum subsp. pallidum (Tp) breaches this barrier through elusive mechanisms and rapidly disseminates throughout the host. We aimed to understand the impact of Tp on the surrounding FN matrix of MEB and the underlying mechanisms of this effect. In this study, immunofluorescence assays (IF) were conducted to assess the integrity of the FN matrix surrounding human microvascular endothelial cell-1 (HMEC-1) with/without Tp co-culture, revealing that only live Tp exhibited the capability to mediate FN matrix disaggregation in HMEC-1. Western blotting and IF were employed to determine the protein levels associated with the FN matrix during Tp infection, which showed the unaltered protein levels of total FN and its receptor integrin α5ß1, along with reduced insoluble FN and increased soluble FN. Simultaneously, the integrin α5ß1-binding protein-intracellular vimentin maintained a stable total protein level while exhibiting an increase in the soluble form, specifically mediated by the phosphorylation of its 39th residue (pSer39-vimentin). Besides, this process of vimentin phosphorylation, which could be hindered by a serine-to-alanine mutation or inhibition of phosphorylated-AKT1 (pAKT1), promoted intracellular vimentin rearrangement and FN matrix disaggregation. Moreover, within the introduction of additional cellular FN rather than other Tp-adhered ECM protein, in vitro endothelial barrier traversal experiment and in vivo syphilitic infectivity test demonstrated that viable Tp was effectively prevented from penetrating the in vitro MEB or disseminating in Tp-challenged rabbits. This investigation revealed the active pAKT1/pSer39-vimentin signal triggered by live Tp to expedite the disaggregation of the FN matrix and highlighted the importance of FN matrix stability in syphilis, thereby providing a novel perspective on ECM disruption mechanisms that facilitate Tp dissemination across the MEB.

The Multifaceted Role of Endothelial Sirt1 in Vascular Aging: An Update.

NAD+-dependent deacetylase sirtuin-1 (Sirt1) belongs to the sirtuins family, known to be longevity regulators, and exerts a key role in the prevention of vascular aging. By aging, the expression levels of Sirt1 decline with a severe impact on vascular function, such as the rise of endothelial dysfunction, which in turn promotes the development of cardiovascular diseases. In this context, the impact of Sirt1 activity in preventing endothelial senescence is particularly important. Given the key role of Sirt1 in counteracting endothelial senescence, great efforts have been made to deepen the knowledge about the intricate cross-talks and interactions of Sirt1 with other molecules, in order to set up possible strategies to boost Sirt1 activity to prevent or treat vascular aging. The aim of this review is to provide a proper background on the regulation and function of Sirt1 in the vascular endothelium and to discuss the recent advances regarding the therapeutic strategies of targeting Sirt1 to counteract vascular aging.

E-Selectin and Asymmetric Dimethylarginine Levels in Adult Cyanotic Congenital Heart Disease: Their Relation to Biochemical Parameters, Vascular Function, and Clinical Status.

Background and Aim: Patients with cyanosis secondary to congenital heart disease (CHD) are characterized by erythrocytosis and increased blood viscosity, which contribute to endothelial dysfunction, increased arterial stiffness, and impaired vascular function, which may affect the final clinical presentation. Asymmetric dimethylarginine (ADMA) and e-selectin (e-sel) are valuable biomarkers for endothelial and vascular dysfunction. Their concentration levels in blood serum have the potential to be an accessible tool that reflects the severity of the disease. We aimed to assess e-sel and ADMA levels and their relationship with the clinical status and endothelial and vascular function. Methods: A cross-sectional study, including 36 adult CHD cyanotic patients [(17 males) (42.3 ± 16.3 years)] with an arterial blood oxygen saturation less than 92% and 20 healthy controls [(10 males) (38.2 ± 8.5 years)], was performed. All the patients underwent a clinical examination, blood testing, and cardiopulmonary tests. Their endothelial function was assessed using the intima media thickness and flow-mediated dilatation. Vascular function, using applanation tonometry methods, was determined using the aortic systolic pressure, aortic pulse pressure, augmentation pressure, augmentation index, pulse pressure amplification, and pulse wave velocity. Results: The concentrations of e-sel and ADMA were significantly higher in the patients with CHD. The E-sel levels correlated positively with red blood cells, hemoglobin concentration, hematocrit, and augmentation pressure; they correlated negatively with blood oxygen saturation, the forced expiratory one-second volume, forced vital capacity, and oxygen uptake. The ADMA levels were found to correlate only with age. Conclusions: The E-sel level, unlike ADMA concentration, reflects the severity of erythrocytosis and hypoxia and, thus, the physical status of patients with cyanotic CHD.

The Combination of Natural Compounds Escin-Bromelain-Ginkgo Biloba-Sage Miltiorrhiza (EBGS) Reduces Platelet Adhesion to TNFα-Activated Vascular Endothelium through FAK Signaling.

Thrombosis is a key process that determines acute coronary syndrome and ischemic stroke and is the leading cause of morbidity and mortality in the world, together with cancer. Platelet adhesion and subsequent activation and aggregation are critical processes that cause thrombus formation after endothelial damage. To date, high hopes are associated with compounds of natural origin, which show anticoagulant action without undesirable effects and can be proposed as supportive therapies. We investigated the effect of the new combination of four natural compounds, escin-bromelain-ginkgo biloba-sage miltiorrhiza (EBGS), on the initial process of the coagulation cascade, which is the adhesion of platelets to activated vascular endothelium. Our results demonstrated that EBGS pretreatment of endothelial cells reduces platelet adhesion even in the presence of the monocyte-lymphocyte population. Our data indicate that EBGS exerts its effects by inhibiting the transcription of adhesion molecules, including P-selectin, platelet membrane glycoprotein GP1b, integrins αV and ß3, and reducing the secretion of the pro-inflammatory cytokines interleukin 6, interleukin 8, and the metalloproteinases MMP-2 and MMP-9. Furthermore, we demonstrated that EBGS inhibited the expression of focal adhesion kinase (FAK), strictly involved in platelet adhesion, and whose activity is correlated with that of integrin ß3. The results shown in this manuscript suggest a possible inhibitory role of the new combination EBGS in the reduction in platelet adhesion to activated endothelium, thus possibly preventing coagulation cascade initiation.

The Relevance of the Endothelium in Cardiopulmonary Disorders.

The endothelium is a cell monolayer that lines vessels and separates tissues from blood flow. Endothelial cells (ECs) have a multitude of functions, including regulating blood flow and systemic perfusion through changes in vessel diameter. When an injury occurs, the endothelium is affected by altering its functions and structure, which leads to endothelial dysfunction, a characteristic of many vascular diseases. Understanding the role that the endothelium plays in pulmonary vascular and cardiopulmonary diseases, and exploring new therapeutic strategies is of utmost importance to advance clinically. Currently, there are several treatments able to improve patients' quality of life, however, none are effective nor curative. This review examines the critical role of the endothelium in the pulmonary vasculature, investigating the alterations that occur in ECs and their consequences for blood vessels and potential molecular targets to regulate its alterations. Additionally, we delve into promising non-pharmacological therapeutic strategies, such as exercise and diet. The significance of the endothelium in cardiopulmonary disorders is increasingly being recognized, making ECs a relevant target for novel therapies aimed at preserving their functional and structural integrity.

Molecular mechanisms of the regulatory action of high-density lipoproteins on the endothelial function.

Endothelial dysfunction underlies the pathogenesis of many diseases, primarily cardiovascular diseases. Epidemiological studies have shown an inverse dependence between the plasma level of high-density lipoproteins (HDL) and cardiovascular diseases. The results of experimental studies indicate that the antiatherogenic effect of HDL is associated not only with their participation in the reverse transport of excess cholesterol, but also with their regulatory effect on the functions of cells of various organs and tissues, including endothelial cells. The purpose of this review is to consider recent data on the participation of plasma receptors and related intracellular signaling pathways in the mechanism of protective effect of HDL on endothelial cell functions. Understanding the mechanisms of cell function regulation under the influence of HDL is an important step for the development of new ways of pharmacological correction of impaired endothelial functions and creation of effective endothelial protection drugs.

Association between endothelial function and skin advanced glycation end-products (AGEs) accumulation in a sample of predominantly young and healthy adults.

BACKGROUND: In populations with chronic disease, skin autofluorescence (SAF), a measure of long-term fluorescent advanced glycation end-products (AGEs) accumulation in body tissues, has been associated with vascular endothelial function, measured using flow-mediated dilation (FMD). The primary aim of this study was to quantify the relationship between endothelial function and tissue accumulation of AGEs in adults from the general population to determine whether SAF could be used as a marker to predict early impairment of the endothelium. METHODS: A cross-sectional study was conducted with 125 participants (median age: 28.5 y, IQR: 24.4-36.0; 54% women). Endothelial function was measured by fasting FMD. Skin AGEs were measured as SAF using an AGE Reader. Participant anthropometry, blood pressure, and blood biomarkers were also measured. Associations were evaluated using multivariable regression analysis and were adjusted for significant covariates. RESULTS: FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In the multivariable analysis, SAF, chronological age, and male sex were independently associated with reduced FMD (B [95% CI]; -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]; 1.40 [0.14, 2.67], respectively), with the multivariable model adjusted R2 = 0.31, P < 0.001. CONCLUSIONS: Higher skin AGE levels, as measured by SAF, were associated with lower FMD values, in a predominantly young, healthy population. Additionally, older age and male participants exhibited significantly lower FMD values, corresponding with compromised endothelial function. These results suggest that SAF, a simple and inexpensive marker, could be used to predict endothelial impairment before the emergence of any structural artery pathophysiology or classic cardiovascular disease risk markers. TRIAL REGISTRATION: The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000821897) and concurrently entered into the WHO International Clinical Trials Registry Platform under the same ID number.