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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. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a multisystemic disorder of pregnancy that not only causes perinatal mortality and morbidity but also has a long-term toll on the maternal and fetal cardiovascular system. Women diagnosed with PE are at greater risk for the subsequent development of hypertension, ischemic heart disease, cardiomyopathy, cerebral edema, seizures, and end-stage renal disease. Although PE is considered heterogeneous, inefficient extravillous trophoblast (EVT) migration leading to deficient spiral artery remodeling and increased uteroplacental vascular resistance is the likely initiation of the disease. The principal pathophysiology is placental hypoxia, causing subsequent oxidative stress, leading to mitochondrial dysfunction, mitophagy, and immunological imbalance. The damage imposed on the placenta in turn results in the "stress response" categorized by the dysfunctional release of vasoactive components including oxidative stressors, proinflammatory factors, and cytokines into the maternal circulation. These bioactive factors have deleterious effects on systemic endothelial cells and coagulation leading to generalized vascular dysfunction and hypercoagulability. A better understanding of these metabolic factors may lead to novel therapeutic approaches to prevent and treat this multisystemic disorder. In this review, we connect the hypoxic-oxidative stress and inflammation involved in the pathophysiology of PE to the resulting persistent cardiovascular complications in patients with preeclampsia. [ABSTRACT FROM AUTHOR]

Summary: Retinopathy and albuminuria are associated with hip fracture risk. We investigated whether these disorders and endothelial dysfunction (which underlies microvascular diseases) were associated with low trabecular bone density. No significant associations were found, suggesting that microvascular diseases are not related to fracture risk through low trabecular bone density. Purpose: Microvascular diseases of the eye, kidney, and brain are associated with endothelial dysfunction and increased hip fracture risk. To explore the basis for higher hip fracture risk, we comprehensively examined whether markers of microvascular disease and/or endothelial dysfunction are related to trabecular bone mineral density (BMD), a proximate risk factor for osteoporotic fractures. Methods: Among 6814 participants in the Multi-Ethnic Study of Atherosclerosis study (MESA), we derived thoracic vertebral trabecular BMD from computed tomography of the chest and measured urine albumin to creatinine ratios (UACR), retinal arteriolar and venular widths, flow mediated dilation (FMD) of the brachial artery after 5 min of ischemia; and levels of five soluble endothelial adhesion markers (ICAM-1, VCAM-1, L-selectin, P-selectin, and E-selectin). Linear regression models were used to examine the association of trabecular BMD with markers of microvascular disease and with markers of endothelial dysfunction. Results: We observed no significant associations of UACR, retinal arteriolar or venular widths, or FMD with BMD. We also observed no statistically significant association of spine trabecular BMD with levels of endothelial adhesion markers. Men and women had largely similar results. Conclusion: We conclude that there is little evidence to connect thoracic spine trabecular BMD to microvascular disorders or to endothelial dysfunction among multi-ethnic middle-aged and older adults. Other factors beyond trabecular BMD (e.g., bone quality or predisposition to falling) may be responsible for the associations of microvascular disease with osteoporotic fractures. [ABSTRACT FROM AUTHOR]

There is evidence to suggest that M‐type phospholipase A2 (PLA2R) antibodies activate the mannose‐binding lectin (MBL) cascade, resulting in glomerular damage and proteinuria in patients with primary membranous nephropathy (PMN). Furthermore, there are few reports indicating that aberrant MBL activation is associated with endothelial dysfunction and accelerated atherosclerosis. While PMN is a common cause of adult nephrotic syndrome, and patients are at increased risk of cardiovascular disease (CVD), there is a lack of research that explores the factors that contribute to this condition. This study aims to determine the MBL levels in PMN and their relation to the clinical activity and endothelial dysfunction in PMN. The MBL levels of 22 biopsy‐confirmed PMN patients were assessed at baseline and after 6 months of immunosuppressive therapy. In order to evaluate endothelial dysfunction in PMN patients, flow‐mediated vasodilation (FMD) was measured at baseline and after treatment. A total of 22 healthy controls were included in this study to measure MBL levels and FMD. A significant difference was observed between MBL levels in PMN patients and healthy controls (p <.01). MBL levels decreased significantly after immunosuppressive therapy (p =.04). The baseline MBL levels and FMD levels exhibited a strong correlation (Spearman correlation coefficient [ρ] = 0.51: p =.01). In conclusion, the study signals the activation of the MBL cascade and its association with endothelial dysfunction in PMN patients. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction (ED) plays a prominent role in the pathogenesis of preeclampsia (PE). There is a need for non-invasive methods to assess endothelial function in preeclamptic patients. In the present study, adropin, autotaxin (ATX), and lysophosphatidic acid (LPA) were evaluated as indicators of ED. Patients diagnosed with PE and healthy pregnant women (n = 42 for each group) were compared. After measuring flow-mediated dilation (FMD), the participants were stratified as ED (+) or ED (−) based on a cut-off value of 6.5%. The PE patients were divided as early/late onset PE and severe/mild PE. Adropin, ATX, and LPA levels were measured, and their relevance to ED was evaluated. Student t, Mann–Whitney U, or ANOVA tests were used for statistics, as appropriate. Adropin levels were diminished in the ED (+) group, whereas ATX and LPA levels were increased. The decrease in adropin levels was more pronounced in severe PE, showing a positive correlation with the FMD. In the logistic regression model, adropin was the only parameter that was an independent variable for the FMD test (P <.001). Adropin measurements in serum may be of value for disease follow-up in patients with PE. [ABSTRACT FROM AUTHOR]

Purpose of Review: Long COVID affects approximately 5 million people in Africa. This disease is characterized by persistent symptoms or new onset of symptoms after an acute SARS-CoV-2 infection. Specifically, the most common symptoms include a range of cardiovascular problems such as chest pain, orthostatic intolerance, tachycardia, syncope, and uncontrolled hypertension. Importantly, these conditions appear to have endothelial dysfunction as the common denominator, which is often due to impaired nitric oxide (NO) mechanisms. This review discusses the role of mechanisms contributing to endothelial dysfunction in Long COVID, particularly in people living with HIV. Recent Findings: Recent studies have reported that increased inflammation and oxidative stress, frequently observed in Long COVID, may contribute to NO dysfunction, ultimately leading to decreased vascular reactivity. These mechanisms have also been reported in people living with HIV. In regions like Africa, where HIV infection is still a major public health challenge with a prevalence of approximately 26 million people in 2022. Specifically, endothelial dysfunction has been reported as a major mechanism that appears to contribute to cardiovascular diseases and the intersection with Long COVID mechanisms is of particular concern. Further, it is well established that this population is more likely to develop Long COVID following infection with SARS-CoV-2. Therefore, concomitant infection with SARS-CoV-2 may lead to accelerated cardiovascular disease. Summary: We outline the details of the worsening health problems caused by Long COVID, which exacerbate pre-existing conditions such as endothelial dysfunction. The overlapping mechanisms of HIV and SARS-CoV-2, particularly the prolonged inflammatory response and chronic hypoxia, may increase susceptibility to Long COVID. Addressing these overlapping health issues is critical as it provides clinical entry points for interventions that could improve and enhance outcomes and quality of life for those affected by both HIV and Long COVID in the region. [ABSTRACT FROM AUTHOR]

Pulmonary Embolism (PE) is a life-threatening condition initiated by the presence of blood clots in the pulmonary arteries, leading to severe morbidity and mortality. Underlying mechanisms involve endothelial dysfunction, including impaired blood flow regulation, a pro-thrombotic state, inflammation, heightened oxidative stress, and altered vascular remodeling. These mechanisms contribute to vascular diseases stemming from PE, such as recurrent thromboembolism, chronic thromboembolic pulmonary hypertension, post-thrombotic syndrome, right heart failure, and cardiogenic shock. Detailing key risk factors and utilizing hemodynamic stability-based categorization, the review aims for precise risk stratification by applying established diagnostic tools and scoring systems. This article explores both conventional and emerging biomarkers as potential diagnostic tools. Additionally, by synthesizing existing knowledge, it provides a comprehensive outlook of the current enhanced PE management and preventive strategies. The conclusion underscores the need for future research to improve diagnostic accuracy and therapeutic effectiveness in PE. [ABSTRACT FROM AUTHOR]

Background and Aim: Endothelial dysfunction is a crucial precursor to atherosclerosis and cardiovascular complications, particularly prevalent in individuals with type 2 diabetes mellitus (T2DM). This study aimed to assess endothelial impairment in T2DM using flow-mediated dilatation (FMD) and to determine its correlation with body mass index (BMI), duration of diabetes, C-reactive protein (CRP) levels, and glycemic control. Materials and Methods: A total of 100 T2DM patients aged thirty to sixty participated. Doppler ultrasonography was used to measure brachial artery FMD, while blood samples were used to assess glycosylated hemoglobin A1c (HbA1c) and CRP levels. Correlations were evaluated using the Pearson correlation coefficient. Result: The duration of diabetes r value is negative 0.866, p-value less than 0.001, CRP levels as "r value" is negative 0.724, "P-value" less than 0.001, and HbA1c levels "r value" is negative 0.722, "P-value" less than 0.001 were observed to have negative relationships with FMD. Additionally, there was a significant association r value was negative 0.342, "P-value" less than 0.001 between BMI and FMD. These results were corroborated by subgroup analyses, which highlighted the intricacy of "endothelial dysfunction" in T2DM and the significance of comprehensively addressing several risk variables. This study elucidates the intricate interplay of metabolic, inflammatory, and vascular factors contributing to "endothelial dysfunction" in T2DM patients. Elevated HbA1c and CRP levels, prolonged diabetes duration, and high BMI were linked to impaired endothelial function, underscoring the importance of holistic risk factor management. Conclusion: For patients with T2DM, maintaining endothelial function and reducing cardiovascular risk require comprehensive treatment plans that target inflammation, obesity, and glycaemic management. Timely intervention and vigilant monitoring of risk factors are crucial to prevent vascular complications in high-risk populations. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) can be a fatal disease characterized by progressive lung scarring. It is still poorly understood how the pulmonary endothelium is involved in the disease pathogenesis. Differences of the pulmonary vasculature between patients and donors were analyzed using transmission electron microscopy, immunohistochemistry, and single-cell RNA sequencing. Vascular barrier resistance, endothelial–immune cell adhesion, and sensitivity to an inflammatory milieu were studied in vitro. Integrity and activation markers were measured by ELISA in human plasma. Transmission electron microscopy demonstrated abnormally swollen endothelial cells (ECs) in fibrotic lungs compared with donors. A more intense CD31 and von Willebrand Factor (vWF) and patchy vascular endothelial (VE)-Cadherin staining in fibrotic lungs supported the presence of a dysregulated endothelium. Integrity markers CD31, VE-Cadherin, Thrombomodulin, and VEGFR-2 (vascular endothelial growth factor receptor-2) and activation marker vWF gene expression was increased in different endothelial subpopulations (e.g., arterial, venous, general capillary, aerocytes) in PF. This was associated with a heightened sensitivity of fibrotic ECs to TNF-α or IFN-γ and elevated immune cell adhesion. The barrier strength was overall reduced in ECs from fibrotic lungs. vWF and IL-8 were increased in the plasma of patients, whereas VE-Cadherin, Thrombomodulin, and VEGFR-2 were decreased. VE-Cadherin staining was also patchy in biopsy tissue and was decreased in plasma samples of patients with PF 6 months after the initial diagnosis. Our data demonstrate highly abnormal ECs in PF. The vascular compartment is characterized by hyperactivation and increased immune cell adhesion, as well as dysfunctional endothelial barrier function. Reestablishing EC homeostasis and function might represent a new therapeutic option for fibrotic lung diseases. [ABSTRACT FROM AUTHOR]

The identification of obese subjects at higher risk for cardiovascular disease (CVD) is required. We aimed to characterize determinants of endothelial dysfunction, the initial step to CVD, in small omental arteries of visceral fat from obese subjects. The influences of analytical parameters and vascular oxidative stress mediated by NADPH-oxidase-2 (NOX2) on endothelial function were determined. Specimens were obtained from 51 obese subjects undergoing bariatric surgery and 14 non-obese subjects undergoing abdominal surgery. Obese subjects displayed reduced endothelial vasodilation to bradykinin (BK). Endothelial vasodilation (pEC50 for BK) among obese subjects was significantly and negatively associated with low-density lipoprotein cholesterol (LDL-c)/high-density lipoprotein cholesterol (HDL-c) ratio (r = -0.510, p = 0.0001) in both women and men, while other metabolic parameters and comorbidities failed to predict endothelial function. The vascular expression of NOX2 was upregulated in obese subjects and was related to decreased endothelial vasodilation (r = −0.529, p = 0.0006, n = 38) and increased oxidative stress (r = 0.783, p = 0.0044, n = 11) in arterial segments. High LDL-c/HDL-c (>2) and high NOX2 (above median) were independently associated with reduced endothelial function, but the presence of both conditions was related to a further impairment. Concomitant elevated LDL-c/HDL-c ratio and high vascular expression of NOX2 would exacerbate endothelial impairment in obesity and could reveal a deleterious profile for cardiovascular outcomes among obese subjects. [ABSTRACT FROM AUTHOR]

Background: Periodontitis, a chronic inflammatory disease, has been associated with an elevated risk of cardiovascular disease (CVD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has emerged as a potential biomarker linking periodontitis, endothelial dysfunction, and CVD. This systematic review aimed to synthesize the existing evidence on the relationship between ADMA, periodontitis, and CVD, and to evaluate ADMA's potential as a biomarker for periodontal disease progression and its correlation with endothelial dysfunction. Methods: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science databases from their inception to March 2023. Observational and interventional studies assessing ADMA levels in patients with periodontitis and/or CVD were included. The methodological quality of the included studies was evaluated using the NIH Quality Assessment Tools. Due to the heterogeneity of the included studies, a qualitative synthesis was performed. Results: Cross-sectional studies consistently demonstrated significantly elevated ADMA levels in patients with periodontitis and CVD compared to healthy controls. The prospective cohort study indicated that successful periodontal treatment was associated with a significant reduction in ADMA levels and concomitant improvement in endothelial function. The pilot cohort study reported a significant decrease in ADMA levels following periodontal therapy in patients with chronic kidney disease. However, the randomized controlled trials did not demonstrate significant alterations in ADMA levels or endothelial function subsequent to periodontal treatment in patients with periodontitis alone. Conclusions: Periodontal treatment may effectively reduce ADMA levels and improve endothelial function, particularly in patients with comorbidities. These findings suggest that ADMA is a promising biomarker linking periodontitis, endothelial dysfunction, and CVD. However, the limitations of this study include the small number of studies, heterogeneity in the study designs, and a lack of long-term follow-up data. Further high-quality, longitudinal studies are required to confirm its clinical utility and elucidate the underlying mechanisms of these relationships. The integration of periodontal care into CVD prevention and management strategies warrants consideration, as it may contribute to mitigating the cardiovascular risk associated with periodontitis. [ABSTRACT FROM AUTHOR]

Abstract Endothelial dysfunction exacerbates hypertension and other vascular complications in diabetes mellitus (DM). Circulating microparticles (MPs) and extracellular vesicles released in patients with DM have emerged as novel regulators of endothelial dysfunction. The obstruction of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications. Their impact on the obstruction of MRs on circulating MPs and endothelial dysfunction in DM remains unclear. DM was induced in mice through a single intravenous dose of streptozotocin (STZ; 200 mg/kg). Esaxerenone (ESAX; 3 mg/kg/day), a MR blocker was administered via diet for 8 weeks. In this study, the aortas of the DM group showed the endothelial dysfunction and the administration of ESAX ameliorated the endothelial-dependent responses. Moreover, ESAX influences the impaired endothelial-dependent responses of DM-derived MPs. Interestingly, MP levels increased in DM whereas decreased after ESAX administration. In the aorta, the DM-derived MPs increased the expression of intercellular adhesion molecule-1 (ICAM-1). ESAX inhibited the adhesion of DM-derived MPs. Moreover, the ICAM-1 inhibitor A205804 shows similar effects as ESAX. These results indicate that the release and adhesion properties of MPs can be partially obstructed by ESAX via the ICAM-1 signaling pathway, which clarifies the other functions beyond the anti-hypertensive effects of ESAX.

Endothelial activation as well as dysfunction is a major factor in atherosclerosis, cardiovascular disorders, and cardiorenal syndrome. Endothelial dysfunction is additionally associated with metabolic syndrome as well as type II diabetes. The hunt for distinctive as well as sensitive biomarkers of endothelial activity and dysfunction may have substantial therapeutic consequences. This review pinpoints the variations in biomarkers that occur between endothelial activation and endothelial dysfunction in cardiovascular illnesses, and then briefly highlights the most significant biomarkers of endothelial activation. Biomarkers of endothelial activation consist of endothelial adhesion molecules, as well as cytokines, and C-reactive protein, along with CD62E++/E-selectin activated endothelial microparticles, and oxidation of low-density lipoproteins, together with asymmetric dimethylarginine as well as endocan. This study also includes an update on the new biomarkers of endothelial dysfunction, such as matrix metalloproteinases (MMP) (e.g., MMP-7, MMP-9), along with ANGPTL2, and endoglin, together with annexin V++ endothelium apoptotic microparticles, and serum homocysteine. Finally, this study stresses the limits of biomarkers of endothelium activation and dysfunction in clinical situations.

Abstract Background It becomes clearer that migraine is associated with vascular risks; however, preclinical vascular involvement is not sufficiently addressed. Evidences point that migraine attacks affect vascular endothelium. The aim of this study was to investigate endothelial dysfunction in migraineurs through assessment of carotid intima-media thickness (CIMT) and flow-mediated dilatation (FMD) of the brachial artery and their correlation with clinical characteristics of migraine, headache severity, and brain magnetic resonance imaging (MRI) findings. Results A statistically significant difference was found between migraineurs and controls where carotid IMT was significantly higher and FMD of the brachial artery was significantly lower in migraineurs compared to controls. Carotid IMT was significantly higher and FMD was significantly lower in chronic migraine compared to episodic migraine patients. Mean IMT values were significantly higher in patients receiving ergots and in patients with subcortical white matter lesions in brain MRI. Mean FMD values were significantly lower in patients receiving ergots. There was a significant negative correlation between FMD and carotid IMT, age of the patients, disease duration, duration of headache attacks, headache frequency, and migraine disability assessment questionnaire (MIDAS) score. There were significant positive correlations between carotid IMT and age of patients, disease duration, headache frequency, MIDAS score, and number of MRI white matter lesions. For diagnosing endothelial dysfunction in migraineurs, the sensitivity and specificity of IMT were 72.5 and 70%, respectively, with a cut-off value of 0.575 mm and that of FMD were 82.5 and 90%, respectively, with a cut-off value of 20.55%. Conclusion Migraine coincides with endothelial dysfunction which promotes atherogenesis and increased risk of cerebral ischemia. FMD could be used as a potential biomarker for endothelial dysfunction in migraine. The affection of IMT and FMD is more in patients receiving ergots which may influence the selection of treatment in migraineurs in the future.

Yining Li, Yulin Chen, Hui Zhang, Weidong Chen, Yan Pan Department of Nephrology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People’s Republic of ChinaCorrespondence: Weidong Chen; Yan Pan, Department of Nephrology, The First Affiliated Hospital of Bengbu Medical University, 287 Changhuai Road, Bengbu, People’s Republic of China, Email cwd2012@163.com; py19841205@163.comPurpose: The glucagon-like peptide-1 receptor agonist (GLP-1RA) is a pharmacological agent utilized for the treatment of diabetes, known for its significant reno protective effects. This study aims to investigate the impact of liraglutide, a representative GLP-1RA medication, on early endothelial dysfunction in diabetic rats and elucidate its underlying mechanisms.Methods: The present study employed a high-fat, high-sugar diet in combination with a single intraperitoneal injection of streptozotocin (STZ) to establish an experimental rat model of diabetes. Subsequently, the therapeutic efficacy of liraglutide on renal injury in this model was evaluated using various doses.Results: Compared to the DKD rats, the rats treated with Liraglutide exhibited significant reductions in levels of blood glucose (Glu), serum creatinine (Scr), and blood urea nitrogen (BUN) (P < 0.05). Furthermore, there was a dose-dependent decrease in urinary protein levels, including 24-hour urinary protein excretion rate and microalbuminuria (m-ALB), with higher doses demonstrating more pronounced therapeutic effects (P < 0.05). In addition, treatment with Liraglutide effectively improved glomerular and interstitial damage, and suppressed the expression of CD31, CD34, and VE-cadherin associated with endothelial cell injury (P < 0.05). Furthermore, Liraglutide administration significantly increased nitric oxide (NO) production (P < 0.05). Moreover, Liraglutide treatment resulted in decreased expression of vascular endothelial growth factor (VEGF), Delta-like ligand-4(Dll4), and Notch2 protein in the Notch2 signaling pathway (P < 0.05).Conclusion: The findings indicate that Liraglutide has a substantial effect on decreasing urinary protein excretion and improving vascular microinflammation, thus alleviating endothelial dysfunction in diabetic nephropathy. This observed mechanism can be attributed to the inhibition of the Dll4/Notch2 signaling pathway.Keywords: diabetic kidney disease, Dll4/Notch2 signaling pathway, endothelial dysfunction, liraglutide, VEGF

The aim of the work was to investigate the dynamics of endothelial markers in patients with arterial hypertension with different cardiovascular risk under the influence of the prescribed treatment during a year of observation. The first group (with a moderate risk of cardiovascular events) included 48 patients with arterial hypertension (AH). The second group consisted of 54 patients with hypertension and a high risk of cardiovascular events, namely type 2 diabetes. Each group of patients was randomized into two subgroups by blood pressure (BP) medication. In patients of subgroup 1a (n=29) and subgroup 2a (n=35) – the main subgroups – the therapy necessarily included the angiotensin II receptor antagonist losartan potas­sium in a dosage of 50-150 mg/day, depending on the blood pressure level. Patients of subgroup 1b (n=19) and subgroup 2b (n=19) – comparison subgroups were treated with antihypertensive drugs of other first-line groups according to the data of the unified clinical protocol for the treatment of hypertension. According to the ROC analysis, it was determined that the dynamics of endothelin-1 (ET-1) indicators after 9 and 12 months of therapy (a decrease of 12% or more from the initial level) can predict the normalization of indicators of the coagulation and anticoagulation systems with indicators of sensitivity and specificity – 85% (95% CI 62.1-96.6%) and 92.9% (95% CI 76.5-98.9%), respectively. A decrease in the level of Willebrand factor (fV) by 23% or more due to such a treatment time can be used as a prognostic sign in determining the regression of endothelial dysfunction with sensitivity – 75% (95% CI 50.9-91.2%), specificity – 100% (95% CI 87.5-100%). According to the given data, both in the group with moderate and with high cardiovascular risk, there is a relationship between endothelial dysfunction (ED) and the duration of hypertension, indicators of the lipid spectrum and abdominal obesity – factors that increase the viscous resistance of the blood circulation, as well as platelet hyperactivity in the bloodstream. We have also established that according to the dynamics of ET-1 indicators after 9 and 12 months of therapy (decrease by 27% or more from the initial level), it is possible to predict the normalization of indicators of the coagulation and anticoagulation systems with indicators of sensitivity – 81.8% (95% CI 59.7-94.7%), specificity – 90.6% (95% CI 75-97.9%). A decrease in the level of fV by 24.5% or more after a year of treatment can be used as a prognostic sign in determining the regression of endothelial dysfunction with sensitivity – 68.2% (95% CI 45.1-86.1%), specificity – 71.9% (95% CI 53.3-86.2%). The obtained results testify to the dominant role of type 2 diabetes as a factor in platelet disorders of hemostasis. Taking into account the positive dynamics of the above-mentioned markers of ED during the year of treatment, their relationship with the reduction of blood pressure, indicators of the lipid spectrum and abdominal obesity, it should be noted the positive effect of angiotensin II receptor blockers (BRA II) as endothelioprotective drugs. Considering the irrefutable literary data about the absence of thrombomodulin in the blood stream, even its insignificant appearance indicates the presence of endothelial dysfunction. Determining the state and dynamics of changes in endothelial function under the influence of prescribed therapy will make it possible to improve the diagnosis of endothelial function disorders and increase the effectiveness of treatment of patients with hypertension and various cardiovascular risks.

Abstract Endometriosis is a prevalent gynecological condition, affecting around 10% of reproductive-age women. Inflammatory processes associated with endometriosis may contribute to endothelial dysfunction. Increased skin accumulation of advanced glycation end-products (AGEs), reflecting arterial stiffness, potentially links endometriosis with elevated risk of cardiovascular events. We hypothesized that patients with endometriosis have impaired endothelial function as well as increased arterial stiffness and AGE skin accumulation, compared to healthy controls. We compared endothelial function, arterial stiffness, and levels of AGEs in patients suffering from endometriosis and in healthy controls. The study included 45 women aged 20 to 40: 21 patients with endometriosis and 24 healthy controls, matched in terms of age, BMI, and blood pressure values. Endo-PAT 2000 device was used for non-invasive assessment of (i) endothelial function, expressed as Reactive Hyperemia Index (RHI), and (ii) arterial stiffness, expressed as Augmentation Index (AI) and Augmentation Index at 75 heart beats/min (AI@75). Endothelial dysfunction was defined as an RHI value ≤ 1.67. AGE Reader device was used for non-invasive evaluation of skin AGE level accumulation. Patients with endometriosis had lower mean RHI values (1.69 ± 0.54 vs. 2.02 ± 0.48, p = 0.037) and a higher prevalence of endothelial dysfunction, (52.4% vs. 20.8%, p = 0.027) compared to healthy controls. Skin AGE level was higher in patients with endometriosis, compared to controls (2.00 ± 0.57 vs. 1.70 ± 0.24, p = 0.013). There were no significant differences in AI and AI@75 between the two groups. Patients with endometriosis have impaired endothelial function and higher AGE skin accumulation, which are well-established preclinical manifestations of increased cardiovascular risk. There is a great need for comprehensive cardiovascular risk assessments in women with endometriosis to prevent the development of potential atherosclerotic-based complications.

INTRODUCTION. In case of polytrauma, an imbalance occurs between substances produced by the endothelium, the rheological properties of the blood are disrupted, the content of procoagulants increases, the permeability of the vascular wall increases, which contributes to thrombus formation and increased tissue hypoxia, and subsequently to the development of multiple organ failure, and, of course, affects the course of traumatic disease, the development of complications and mortality. However, specific markers of endothelial dysfunction and their levels, by which it is possible to reliably predict the course of traumatic disease in severe combined closed abdominal trauma for the appropriate pathogenetic treatment have not yet been determined.AIM OF THE STUDY. To determine the significance of some markers of endothelial dysfunction (C-reactive protein, von Willebrand factor, the number of desquamated endothelial cells in the blood) in combined blunt abdominal trauma to predict the likelihood of complications and adverse outcomes.MATERIAL AND METHODS. The main group consisted of 31 patients with severe combined blunt abdominal trauma, the comparison group consisted of 5 patients operated on for large ventral hernias. All patients underwent blood tests for C-reactive protein, von Willebrand factor, the number of desquamated endothelial cells.RESULTS. The level of all three considered markers of endothelial dysfunction in severe abdominal trauma significantly differs from that in operated non-traumatized patients, which allows differential diagnostics to be made between abdominal wall contusion and damage to internal organs; extremely high values suggest an unfavorable course of traumatic disease and a high probability of a fatal outcome.CONCLUSION. Taking into account that the development of traumatic disease is based on damage to the vascular endothelium, it is necessary to consider as prognostic indicators changes in the level of activity of C-reactive protein, von Willebrand factor, desquamated endothelial cells in patients with severe combined blunt abdominal trauma.

Abstract There is a lack of in-depth research on the impacts and changes in chronic psychological stress (CPS) on the cardiovascular system after acute myocardial infarction (AMI). This study aims to explore the comorbid mechanism and dynamic evolution of AMI exposed to CPS. 120 Wistar rats were randomly divided into Sham Operation group, Sham Operation + Chronic Unpredictable Mild Stress (CUMS) group, AMI group and AMI + CUMS group, with each group further divided into subgroups at days 7, 14, and 28. The AMI model was created by ligating the left anterior descending coronary artery, and CUMS model was used to induce CPS in rats. Behavioral changes were assessed through open field tests and sucrose preference tests. Cardiac function and structure were evaluated via echocardiography. The serum levels of TNFα, IL-6, NO, ET, CK-MB, cTNT, and ANP were measured using assay kits. Pathological changes in cardiac and brain tissues were observed under an optical microscope. Comparative analysis across different models revealed that CUMS significantly reduced behavioral activities in rats, with an interaction between CUMS and AMI affecting total distance (P

Abstract Background Endothelial dysfunction is an integral pathophysiologic mechanism in sickle cell disease (SCD), and can lead to many complications. Sleep-disordered breathing (SDB) is a SCD complication with diverse incidence and pathophysiology. This study aimed to determine the prevalence of SDB in children with SCD and to assess its relation to endothelial dysfunction. Methods Sixty children with SCD and 60 healthy controls were enrolled. The levels of TNF-α, IL-6, and IL-17A were evaluated in the entire cohort using enzyme-linked immunosorbent assay (ELISA) kits. Polysomnography (PSG) was performed for all SCD patients after completion of the Pediatric Sleep Questionnaire (PSQ). Results TNF-α, IL-6, and IL-17A levels were significantly greater in children with SCD than in controls (p-values

Abstract Background The formation of secondary organic aerosols (SOA) by atmospheric oxidation reactions substantially contributes to the burden of fine particulate matter (PM2.5), which has been associated with adverse health effects (e.g., cardiovascular diseases). However, the molecular and cellular effects of atmospheric aging on aerosol toxicity have not been fully elucidated, especially in model systems that enable cell-to-cell signaling. Methods In this study, we aimed to elucidate the complexity of atmospheric aerosol toxicology by exposing a coculture model system consisting of an alveolar (A549) and an endothelial (EA.hy926) cell line seeded in a 3D orientation at the air‒liquid interface for 4 h to model aerosols. Simulation of atmospheric aging was performed on volatile biogenic (β-pinene) or anthropogenic (naphthalene) precursors of SOA condensing on soot particles. The similar physical properties for both SOA, but distinct differences in chemical composition (e.g., aromatic compounds, oxidation state, unsaturated carbonyls) enabled to determine specifically induced toxic effects of SOA. Results In A549 cells, exposure to naphthalene-derived SOA induced stress-related airway remodeling and an early type I immune response to a greater extent. Transcriptomic analysis of EA.hy926 cells not directly exposed to aerosol and integration with metabolome data indicated generalized systemic effects resulting from the activation of early response genes and the involvement of cardiovascular disease (CVD) -related pathways, such as the intracellular signal transduction pathway (PI3K/AKT) and pathways associated with endothelial dysfunction (iNOS; PDGF). Greater induction following anthropogenic SOA exposure might be causative for the observed secondary genotoxicity. Conclusion Our findings revealed that the specific effects of SOA on directly exposed epithelial cells are highly dependent on the chemical identity, whereas non directly exposed endothelial cells exhibit more generalized systemic effects with the activation of early stress response genes and the involvement of CVD-related pathways. However, a greater correlation was made between the exposure to the anthropogenic SOA compared to the biogenic SOA. In summary, our study highlights the importance of chemical aerosol composition and the use of cell systems with cell-to-cell interplay on toxicological outcomes. Graphical Abstract

Background. Blepharitis is one of the most common eye diseases: it accounts for 23.3 % of the total number of patients with inflammatory eye diseases worldwide. 40.2 % of these patients seek outpatient care. The incidence of blepharitis is 1.5–2 times higher in women than in men. The leading factors in the development of blepharitis are both general (gastrointestinal tract diseases, diabetes mellitus, hypertension, systemic use of corticosteroids, etc.) and local (atopic and seborrheic dermatitis or rosacea). The main causative agents of this disease are Staphylococcus spp. (S. aureus, S. epidermidis). As a rule, the disease manifests itself in patients aged 30–50 years, while in women aged 40 to 45 years, 80 % of blepharitis are of staphylococcal origin. Currently, there are reports in the literature about apotential link between Helicobacter pylori infection and the development of chronic blepharitis, but the data are very contradictory.The aim of the study. To analyze the features of the relationship between Helicobacter pylori and inflammatory eyelid diseases.Materials and methods. We conducted a search and analysis of literary sources in the Web of Science, PubMed and Google Scholar databases, as well as in the Russian Science Citation Index database for the period from 2000 to 2022.Conclusion. The review analyzes and summarizes the pathogenic mechanisms of the relationship between chronic blepharitis and Helicobacter pylori. We carried out an analysis of numerous studies, which give grounds to assume a possible role of Helicobacter pylori infection in the development and course of inflammatory eyelid diseases (blepharitis). The main pathogenic aspects in these studies are: chronic inflammation of the eyelids and gastrointestinal tract (antigenic mimicry); excretion of toxic substances from the oral cavity (ammonia, hydrogen nitrite, hydrogen cyanide and other substances causing indirect inflammation of the conjunctiva and eyelid cartilage); the presence of Helicobacter pylori in tears.

Background. Currently, the pathophysiological mechanisms of acute damage to organs and systems caused by coronavirus infection have been studied quite fully, but the mechanisms underlying the clinical manifestations of long COVID have not yet been accurately described. The mechanisms of persistence of a number of symptoms in patients who have had COVID-19 and the role of systemic inflammation and endotoxemia markers in it remain a understudied aspect and a promising direction for further studying.The aim of the study. To assess the markers of systemic inflammation, endotoxin-releasing systems, intestinal permeability and endothelial dysfunction in patients with long COVID at the stage of health resort treatment.Methods. The study included 32 patients who had recovered from coronavirus infection and were undergoing health resort treatment in the pulmonology department of the I.M. Sechenov Academic Research Institute for Physical Therapy, Medical Climatology and Rehabilitation. We also selected a control group (n = 20). All patients underwent peripheral blood analysis to detect the levels of markers of systemic inflammation, endotoxin-releasing systems, intestinal permeability, endothelial dysfunction and vasoconstrictor agents: C-reactive protein (CRP), lipopolysaccharide-binding protein (LPB), tissue-type plasminogen activator (tPA), zonulin, bactericidal/ permeability-increasing protein (BPI), vasopressors of angiotensin 2 and endothelin (EDN1).Results. Patients who had recovered from coronavirus infection had a statistically significant increase in the levels of CRP (3.4 [2.56; 4.0] mg/l), LBP (18.46 [14.0; 25.5] ng/ml), tPA (0.07 [0.02; 0.32] ng/ml), angiotensin 2 (133.3 [63.0; 503.7] pg/ml) and a decrease in the level of BPI (1576 [276; 3588] pg/ml) (p < 0.05).Conclusion. A statistically significant increase in markers of systemic inflammation, endotoxinemia, and vasoconstrictor agents in patients with long COVID indicates an imbalance in endotoxin-binding and endotoxin-releasing systems in patients who have had coronavirus infection. Further study of the described markers is necessary to improve approaches to long-term personalized therapy for this category of patients.

Introduction. Cardiovascular diseases are still the leading cause of death worldwide. In contrast to men, in women, cardiovascular diseases, such as coronary artery disease, acute cerebrovascular accident, and thrombosis of various localization, develop later in life. A fold rise in risk begins during the menopausal transition. Given the increase in the postmenopausal period of a woman's life, it seems interesting to search for new methods of early prevention of cardiometabolic complications already in perimenopause. Aim. To optimize early non-hormonal prevention of endothelial dysfunction and perimenopausal cardiovascular complications. Materials and methods. A prospective study included 50 patients aged 45–55 years in perimenopause without obesity and other somatic or gynecological disorders with menopausal syndrome of varying severity. Patients in group 1 (n=25) received combined non-hormonal treatment of menopausal symptoms and prevention of cardiovascular complications [sulodexide 250 lipasemic units (LU) 2 times a day + phytoestrogen (cimicifuga extract) 1 capsule 2 times a day]. In group 2 (n=25), patients received only phytoestrogen according to the same regimen. Results. After 1 year of observation, the mean thickness of the intima-media complex of the common carotid artery in group 1, in which patients received complex course therapy including sulodexide (Vessel Due F), decreased by 3.7%, and in group 2 increased by 26.8%. In group 1, it was found that after 1 year of regular use, treatment contributed to a decrease in blood fibrinogen level by 11.8% and an increase in thrombin time by 24.5%, which, in combination with a decrease in prothrombin concentration and an increase in activated partial thromboplastin time by 4.7 s, indicates a pronounced therapeutic effect on the hemostasis system. Conclusion. All markers of early atherosclerosis and vascular complications progress during postmenopause and with increasing age. However, complex protective therapy, including glycosaminoglycans sulodexide), can slow down this progression while improving patients' quality of life. Non-hormonal complex therapy can not only neutralize menopausal symptoms but also prevent long-term vascular complications caused by increasing age and the lack of estrogen-protective effect.

Background and Aim: Endothelial dysfunction is a crucial precursor to atherosclerosis and cardiovascular complications, particularly prevalent in individuals with type 2 diabetes mellitus (T2DM). This study aimed to assess endothelial impairment in T2DM using flow-mediated dilatation (FMD) and to determine its correlation with body mass index (BMI), duration of diabetes, C-reactive protein (CRP) levels, and glycemic control. Materials and Methods: A total of 100 T2DM patients aged thirty to sixty participated. Doppler ultrasonography was used to measure brachial artery FMD, while blood samples were used to assess glycosylated hemoglobin A1c (HbA1c) and CRP levels. Correlations were evaluated using the Pearson correlation coefficient. Result: The duration of diabetes r value is negative 0.866, p-value less than 0.001, CRP levels as “r value” is negative 0.724, “P-value” less than 0.001, and HbA1c levels “r value” is negative 0.722, “P-value” less than 0.001 were observed to have negative relationships with FMD. Additionally, there was a significant association r value was negative 0.342, “P-value” less than 0.001 between BMI and FMD. These results were corroborated by subgroup analyses, which highlighted the intricacy of “endothelial dysfunction” in T2DM and the significance of comprehensively addressing several risk variables. This study elucidates the intricate interplay of metabolic, inflammatory, and vascular factors contributing to “endothelial dysfunction” in T2DM patients. Elevated HbA1c and CRP levels, prolonged diabetes duration, and high BMI were linked to impaired endothelial function, underscoring the importance of holistic risk factor management. Conclusion: For patients with T2DM, maintaining endothelial function and reducing cardiovascular risk require comprehensive treatment plans that target inflammation, obesity, and glycaemic management. Timely intervention and vigilant monitoring of risk factors are crucial to prevent vascular complications in high-risk populations.

Zhongsheng Zhu1,2 1Department of Cardiology, Guangming Traditional Chinese Medicine Hospital of Pudong New Area, Shanghai, 201321, People’s Republic of China; 2Department of Cardiology, Shanghai Pudong Hospital Affiliated to Fudan University, Shanghai, 201300, People’s Republic of ChinaCorrespondence: Zhongsheng Zhu, Department of Cardiology, Guangming Traditional Chinese Medicine Hospital of Pudong New Area, 339 Dongmen Ave, Pudong, Shanghai, 201321, People’s Republic of China, Tel +86-18117209753, Email drzzs66@163.comBackground: Arterial stiffness is associated with accelerated progression of atherosclerosis and plaque rupture. Lysyl oxidase-like 2 (LOXL2) plays a vital role in inflammatory responses, matrix deposition and arterial stiffness. This study assessed the correlation between the serum LOXL2 concentration and disease severity, inflammation, and endothelial dysfunction of coronary artery disease (CAD).Methods: The study included 143 CAD patients and 150 non-CAD patients who underwent coronary angiography. Medical records, demographic and clinical baseline parameters were collected. Serum LOXL2 levels were measured using an ELISA kit.Results: CAD patients had higher serum LOXL2 levels than non-CAD patients, and LOXL2 levels were associated with severity of coronary lesions. Serum LOXL2 level was positively correlated with low-density lipoprotein cholesterol (LDL-C) (r=0.161, P=0.054), systolic blood pressure (SBP) (r=0.175, P=0.036), high-sensitivity C-reactive protein (hs-CRP) (r=0.177, P=0.035), intima-media thickness (IMT) (r=0.190, P=0.023), and brachial-ankle pulse wave velocity (baPWV) (r=0.203, P=0.015), while negatively associated with high-density lipoprotein cholesterol (HDL-C) (r=− 0.191, P=0.023) and flow-mediated dilation (FMD) (r=− 0.183, P=0.028) in CAD patients. Multivariate logistic regression showed that LOXL2 is independently correlated with LDL-C (OR=3.380; 95% CI=1.258– 9.082; P=0.016), hs-CRP (OR=10.988; 95% CI=1.962– 61.532; P=0.006), TC (OR=2.229; 95% CI=1.005– 4.944; P=0.049), IMT (OR=72.719; 95% CI=2.313– 2286.008; P=0.015), and baPWV (OR=1.002; 95% CI=1.001– 1.004; P=0.005) in CAD patients. The receiver operating characteristic (ROC) curve showed that the best cut-off for CAD as serum LOXL2 is 275.35 pg/mL, with sensitivity and specificity of 77.6% and 84%, respectively.Conclusion: Our data demonstrated that LOXL2 could be a potential biomarker and independent risk factor for CAD patients.Keywords: coronary artery disease, CAD, atherosclerosis, endothelial dysfunction, arterial stiffness, LXOL2

Introduction. The influence of the length of the number of CAG repeats in the androgen receptor gene (nCAG AR) on endothelial dysfunction (EnD) is currently understudied.Objective. The study aimed to evaluate the relationship between the nCAG AR and the dynamics of biochemical and ultrasound markers of EnD in men with functional hypogonadism and type 2 diabetes mellitus (T2DM) receiving testosterone replacement therapy (TRT).Materials & methods. This study included 45 hypogonadal men with T2DM, receiving TRT for 1 year. Patients were assessed for carbohydrate and lipid metabolism parameters; total and free T; sex hormone-binding globulin; biochemical markers of EnD (NO, eNOS3, endothelin) and the nCAG AR; brachial artery (BA) vasoreactivity. Patients were divided into 3 groups: group I — 9 men with nCAG AR < 19; group II — 27 men with nCAG AR > 19 – 24; and group III — 9 men with nCAG AR >24.Results. Patients with nCAG AR < 19 exhibited a 2-fold greater and faster increase in BA vasoreactivity on TRT compared to patients with nCAG AR 19-24 and 3-fold greater than men with nCAG AR >24 (p < 0.05). Patients with nCAG AR < 19 also demonstrated the most pronounced rise in NO and eNOS3 on TRT compared to men with nCAG AR > 24. Patients with nCAG AR < 19 experienced the most pronounced decreases in weight, waist circumference, and HbA1c on TRT compared to other patients (p < 0.05).Conclusion. The nCAG AR length significantly affects the response to TRT in men with hypogonadism and T2DM. The most significant improvements are seen in patients with short nCAG AR.

Diabetic retinopathy(DR), the most common ocular complication of diabetes, is one of the major causes of vision impairment and even blindness among the working population as well as middle-aged and elderly individuals. In the diabetic microvascular system, hyperglycemia damages retinal endothelial cells, enhances vascular permeability and disrupts the blood-retinal barrier through different mechanisms, all of which result in endothelial dysfunction. Retinal vascular dysfunction caused by multifactors, such as peroxisome proliferator-activated receptor-y disruption, oxidative stress, inflammation, increased advanced glycation end products and their receptors, and microRNA dysregulation can cause vascular endothelial damage, accelerate retinal endothelial dysfunction, lead to the progression of DR. Therefore, the available date and the contributors in the pathophysiology of DR are reviewed with a special emphasis on the retinal endothelial dysfunction, for a better understanding of the molecular cellular mechanism in the development of DR, to analyze the challenges in the treatment of DR and to provide new ideas and strategies for the clinical management and treatment of DR.

The availability of a wide range of flavored e-cigarettes is one of the primary reasons for vaping initiation and persistent use among adolescents and young people. This plethora of flavors available on the market are crafted using different flavoring agents such as cinnamaldehyde, vanillin, benzaldehyde, ethyl maltol, menthol, and dimethylpyrazine. Recent studies have brought to light the potential risks associated with e-cigarette flavoring agents and their effects on various organ systems, both with and without nicotine. Research has demonstrated that flavoring agents can induce inflammation, endothelial dysfunction, epithelial barrier disruption, oxidative stress, DNA damage, electrophysiological alterations, immunomodulatory effects, and behavioral changes, even independently of nicotine. Notably, these negative outcomes adversely affect cardiovascular system by reducing cell viability, decreasing endothelial nitric oxide synthase, nitric oxide bioavailability, soluble guanylyl cyclase activity and cyclic guanosine monophosphate accumulation, impairing endothelial proliferation and tube formation, and altering vasoreactivity resulting in vascular dysfunction. In the heart, these agents decrease parasympathetic activity, induce depolarization of resting membrane potential, loss of rhythmicity, increase isovolumic relaxation time, and change in ventricular repolarization and ventricular tachyarrhythmias. It is found that the specific response elicited by flavoring agents in different organ systems varies depending on the flavor used, the concentration of the flavoring agent, and the duration of exposure. However, the literature on the effects of flavoring agents is currently limited, emphasizing the need for more preclinical and randomized clinical trials to gain a deeper understanding and provide further evidence of the harmful effects of flavored e-cigarette use. In summary, recent research suggests that flavoring agents themselves can have detrimental effects on the body. To fully comprehend these effects, additional preclinical and clinical studies are needed to explore the risks associated with flavored e-cigarette usage.

Cerebral small vessel disease (cSVD) refers to the age-dependent pathological processes involving the brain small vessels and leading to vascular cognitive impairment, intracerebral hemorrhage, and acute lacunar ischemic stroke. Despite the significant public health burden of cSVD, disease-specific therapeutics remain unavailable due to the incomplete understanding of the underlying pathophysiological mechanisms. Recent advances in neuroimaging acquisition and processing capabilities as well as findings from cSVD animal models have revealed critical roles of several age-dependent processes in cSVD pathogenesis including arterial stiffness, vascular oxidative stress, low-grade systemic inflammation, gut dysbiosis, and increased salt intake. These factors interact to cause a state of endothelial cell dysfunction impairing cerebral blood flow regulation and breaking the blood brain barrier. Neuroinflammation follows resulting in neuronal injury and cSVD clinical manifestations. Impairment of the cerebral waste clearance through the glymphatic system is another potential process that has been recently highlighted contributing to the cognitive decline. This review details these mechanisms and attempts to explain their complex interactions. In addition, the relevant knowledge gaps in cSVD mechanistic understanding are identified and a systematic approach to future translational and early phase clinical research is proposed in order to reveal new cSVD mechanisms and develop disease-specific therapeutics. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular diseases are the leading causes of morbidity and mortality worldwide. In our previous study, a panel of miRNA including miR-134-5p was deregulated in young acute coronary syndrome (ACS) patients. However, the roles of these ACS-associated miRNAs in endothelial dysfunction, an early event preceding atherosclerosis, remain to be investigated. In the present study, human aortic endothelial cells (HAECs) were treated with 7-ketocholesterol (7-KC) to induce endothelial dysfunction. Following treatment with 20 mg/ml 7-KC, miR-134-5p was significantly up-regulated and endothelial nitric oxide synthase (eNOS) expression was suppressed. Endothelial barrier disruption was evidenced by the deregulation of adhesion molecules including the activation of focal adhesion kinase (FAK), down-regulation of VE-cadherin, up-regulation of adhesion molecules (E-selectin and ICAM-1), increased expression of inflammatory genes (IL1B, IL6 and COX2) and AKT activation. Knockdown of miR-134-5p in 7-KC-treated HAECs attenuated the suppression of eNOS, the activation of AKT, the down-regulation of VE-cadherin and the up-regulation of E-selectin. In addition, the interaction between miR-134-5p and FOXM1 mRNA was confirmed by the enrichment of FOXM1 transcripts in the pull-down miRNA-mRNA complex. Knockdown of miR-134-5p increased FOXM1 expression whereas transfection with mimic miR-134-5p decreased FOXM1 protein expression. In summary, the involvement of an ACS-associated miRNA, miR-134-5p in endothelial dysfunction was demonstrated. Findings from this study could pave future investigations into utilizing miRNAs as a supplementary tool in ACS diagnosis or as targets for the development of therapeutics.

The assessment of endothelial dysfunction and free radical homeostasis parameters were performed in 92 women, aged 45 to 69 years, divided into the following groups: women without COVID-19 (unvaccinated, no antibodies, control); women with acute phase of COVID-19 infection (main group, COVID-19+); 12 months post COVID-19+; women with anti-SARS-CoV-2 IgG with no symptoms of COVID-19 in the last 12 months (asymptomatic COVID-19). Compared to the control, patients of the main group had lower glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities, decreased advanced glycation end products (AGEs) level, higher glutathione reductase (GR) activity, and higher glutathione S transferases pi (GSTpi), thiobarbituric acid reactants (TBARs), endothelin (END)-1, and END-2 concentrations (all p ≤ 0.05). The group with asymptomatic COVID-19 had lower 8-OHdG and oxidized glutathione (GSSG) levels, decreased total antioxidant status (TAS), and higher reduced glutathione (GSH) and GSH/GSSG levels (all p ≤ 0.05). In the group COVID-19+, as compared to the group without clinical symptoms, we detected lower GPx and SOD activities, decreased AGEs concentration, a higher TAS, and greater GR activity and GSTpi and TBARs concentrations (all p ≤ 0.05). The high content of lipid peroxidation products 12 months post COVID-19+, despite decrease in ENDs, indicates long-term changes in free radical homeostasis. These data indicate increased levels of lipid peroxidation production contribute, in part, to the development of free radical related pathologies including long-term post COVID syndrome.

Erectile dysfunction (ED) is a prevalent condition affecting men’s sexual health, with oxidative stress (OS) having recently been identified as a significant contributing causative factor. This narrative review aims to elucidate the role of OS in the pathophysiology of ED, focusing on impact, mechanisms, and potential therapeutic interventions. Key findings indicate that OS disrupts endothelial function and nitric oxide (NO) signaling, crucial for erectile function. Various sources of reactive oxygen species (ROS) and their detrimental effects on penile tissue are discussed, including aging, diabetes mellitus, hypertension, hyperlipidemia, smoking, obesity, alcohol consumption, psychological stress, hyperhomocysteinemia, chronic kidney disease, and sickle cell disease. Major sources of ROS, such as NADPH oxidase, xanthine oxidase, uncoupled endothelial NO synthase (eNOS), and mitochondrial electron transport, are identified. NO is scavenged by these ROS, leading to endothelial dysfunction characterized by reduced NO availability, impaired vasodilation, increased vascular tone, and inflammation. This ultimately results in ED due to decreased blood flow to penile tissue and the inability to achieve or maintain an erection. Furthermore, ROS impact the transmission of nitrergic neurotransmitters by causing the death of nitrergic neurons and reducing the signaling of neuronal NO synthase (nNOS), exacerbating ED. Therapeutic approaches targeting OS, including antioxidants and lifestyle modifications, show promise in ameliorating ED symptoms. The review underscores the need for further research to develop effective treatments, emphasizing the interplay between OS and vascular health in ED. Integrating pharmacological and non-pharmacological strategies could enhance clinical outcomes for ED patients, advocating for OS management in ED treatment protocols to improve patient quality of life.

Abstract Background Endothelial cellular senescence is emerging as a key mechanism of age-related vascular dysfunction. Disruption of the endothelium glycocalyx and shedding of the syndecan (SDC) ectodomains have been associated with several age-related diseases. Although SDC4 is highly expressed in endothelial cells, its levels and shedding in senescent endothelial cells and vascular endothelial dysfunction associated with aging are still unknown. Methods To assess whether SDC4 expression was affected by inflammatory conditions, we evaluated its levels in young human umbilical vein endothelial cells (HUVECs) treated with TNF-α at a concentration of 50 ng/mL for 24 h and in cells undergoing replicative senescence. Plasma levels of SDC4 were evaluated in two previously recruited cohorts of (i) subjects with type 2 diabetes (T2D, n = 110) followed for a median of 16.8 years and age- and gender-matched healthy subjects (n = 100), and (ii) middle-aged subjects with mild-to-moderate dyslipidemia. Binomial logistic regression was used to assess whether SDC4 levels could be prognostic for major adverse cardiovascular events (MACE). Results In the in vitro study, we showed that HUVECs, when exposed to TNF-α or undergoing replicative senescence, exhibited elevated expression levels of SDC4 and matrix metallopeptidase 9 (MMP-9), as well as increased shedding of SDC4 into the extracellular microenvironment, in comparison to actively proliferating young HUVECs. Analysis of human samples revealed that patients with T2D without complications exhibited higher SDC4 levels compared to healthy controls and those with T2D vascular complications. In particular, patients with a history of major adverse cardiovascular events (MACE) had lower SDC4 levels. The longitudinal evaluation revealed that higher SDC4 levels predict the onset of new MACE during a 16.8-year follow-up. In the second cohort, no significant association was observed between SDC4 and endothelial dysfunction, assessed by flow-mediated dilation (FMD) or nitric oxide metabolites. SDC4 levels correlated positively with C-reactive protein (CRP) in both cohorts and with PAI-1 in the cohort of patients with T2D. Conclusion Overall, we conclude that the shedding of SDC4 from endothelial cells increases under acute (TNF-α treatment) and chronic (senescence) inflammatory conditions and that increased circulating SDC4 levels are associated with systemic inflammation in pathological aging.

Abstract Our aim was to explore possible relationships between serum levels of biomarkers in patients with hand-arm vibration injury in relation to the severity of the vascular, i.e., Raynaud’s phenomenon (RP), and neurosensory manifestations, the current exposure level, and the duration of exposure. This study was of case series design and involved 92 patients diagnosed with hand-arm vibration injury. Jonckheere’s trend test was used to assess any association between serum levels of biomarkers and RP as well as neurosensory manifestations, graded by the International Consensus Criteria. Generalized linear models with adjustment for possible confounders were also used for associations between serum levels of biomarkers and; (1) severity of RP recorded as the extent of finger blanching calculated with Griffin score, (2) vibration perception thresholds, (3) magnitude of current exposure as [A(8); (m/s2)] value, and (4) the duration of exposure in years. Serum levels of thrombomodulin, von Willebrand factor, calcitonin gene related peptide (CGRP), heat shock protein 27, and caspase-3 were positively associated with severity of RP. Serum levels of CGRP were positively associated with the neurosensory component. No associations with exposure were shown for these biomarkers. For Intercellular adhesion molecule 1 and monocyte chemoattractant protein 1, no associations were found with neither severity nor exposure. Levels of serum biomarkers associated with endothelial injury or dysfunction, inflammation, vasodilation, neuroprotection, and apoptosis were positively associated with the severity of hand-arm vibration injury.

Paeoniflorin (Pae) can improve diabetes mellitus (DM), especially endothelial dysfunction induced by high glucose (HG). Molecularly, the mechanism pertinent to Pae and DM lacks further in-depth research. Hence, this study determined the molecular mechanism of Pae in treating DM through network pharmacology. The target of Pae was analyzed by TCMSP database, and DM-related genes were dissected by Genecards database and Omim database. PPI network was constructed for cross targets through Cytoscape 3.9.1 and STRING platform. GO and KEGG analyses were carried out on the cross targets. Protein molecular docking verification was completed by AutoDockTools and Pymol programs. Human umbilical vein endothelial cells (HUVECs) were separately treated with HG, Pae (5, 10, 20 μM) and/or HRAS overexpression plasmids (oe-HRAS). The cell viability, apoptosis and the protein expressions of HRAS and Ras-GTP were evaluated. There were 50 cross targets between Pae and DM, and VEGFA, EGFR, HRAS, SRC and HSP90AA1 were the key genes identified by PPI network analysis. GO and KEGG analyses revealed signal paths such as Rap1 and Ras. Molecular docking results confirmed that Pae had a good binding ability with key genes. In HG-treated HUVECs, Pae dose-dependently facilitated cell viability, attenuated cell apoptosis, and dwindled the expressions of HRAS and Ras-GTP, but these effects of Pae were reversed by oe-HRAS. In conclusion, Pae regulates the viability and apoptosis of HG-treated HUVECs by inhibiting the expression of HRAS.

Liver fibrosis is an important step in the transformation of chronic liver disease into cirrhosis and liver cancer, and structural changes and functional disorders of liver sinusoidal endothelial cells (LSECs) are early events in the occurrence of liver fibrosis. Therefore, it is necessary to identify the key regulatory genes of endothelial dysfunction in the process of liver fibrosis to provide a reference for the diagnosis and treatment of liver fibrosis. In this study, we identified 230 common differentially expressed genes (Co-DEGs) by analyzing transcriptomic data of primary LSECs from three different liver fibrosis mouse models (carbon tetrachloride; choline-deficient, l-amino acid-defined diet; and nonalcoholic steatohepatitis). Enrichment analysis revealed that the Co-DEGs were mainly involved in regulating the inflammatory response, immune response, angiogenesis, formation and degradation of the extracellular matrix, and mediating chemokine-related pathways. A Venn diagram analysis was used to identify 17 key genes related to the progression of liver cirrhosis. Regression analysis using the Lasso–Cox method identified genes related to prognosis among these key genes: SOX4, LGALS3, SERPINE2, CD52, and LPXN. In mouse models of liver fibrosis (bile duct ligation and carbon tetrachloride), all five key genes were upregulated in fibrotic livers. This study identified key regulatory genes for endothelial dysfunction in liver fibrosis, namely SOX4, LGALS3, SERPINE2, CD52, and LPXN, which will provide new targets for the development of therapeutic strategies targeting endothelial dysfunction in LSECs and liver fibrosis.

Objective To investigate the expression levels of platelet microparticles(PMPs) in patients with diabetic nephropathy (DN) and their relationship with renal injury. Methods Thirty DN patients, 30 T2DM patients without DN and 30 healthy controls were enrolled. Flow cytometry was used to detect the quantity and phenotype of PMPs, and ELISA was used to measure the levels of plasma renin, angiotensin Ⅱ (angiotoninⅡ, AngⅡ), vascular endothelial growth factor (vascular endothelial growth factor, VEGF) and transforming growth factor-β1(transforming growth factor-β1, TGF-β1). Kidney function was determined by blood biochemistry. Results The quantity of PMPs in the DN group was (1 564±346) particles/μL, which was significantly higher than that in the non-DN group (1 246±312) particles/μL and the control group (1 223±299) particles/μL (P

Abstract Objective To examine the influences and mechanisms of MicroRNA-19a-3p (miR-19a-3p) on endothelial dysfunction in atherosclerosis. Methods An analysis of miR-19a expression was carried out using the Gene Expression Omnibus (GEO) database. The effect of miR-19a-3p on endothelial function in HUVECs was evaluated by miR-19a-3p overexpression under TNF-α treatment. Luciferase assays were performed to explore the potential target genes. Overexpression of junctional protein associated with coronary artery disease (JCAD) was used to examine the effects of miR-19a-3p on cell adhesion, and proliferation. Results MiR-19a-3p expression in endothelial cells decreased after exposure to TNF-α and/or oscillatory flow, consistent with the expression change of miR-19a-3p found in atherosclerotic plaques. Additionally, endothelial cell dysfunction and inflammation were significantly diminished by miR-19a-3p overexpression but markedly exacerbated by miR-19a-3p inhibition. MiR-19a-3p transfection significantly decreased the expression of JCAD by binding to the 3’-UTR of JCAD mRNA. Furthermore, the protective effect of miR-19a-3p against endothelial cell dysfunction and inflammation was achieved by regulating JCAD and was closely linked to the Hippo/YAP signaling pathway. Conclusion MiR-19a-3p expression is a crucial molecular switch in the onset of atherosclerosis and miR-19a-3p overexpression is a possible pharmacological therapeutic strategy for reversing the development of atherosclerosis.

Aim. To study the relationship between myocardial contractility impairment in chronic coronary syndrome and the state of coronary flow reserve, the degree of systemic inflammation and endothelial dysfunction. Materials and methods. We examined 120 patients with stable angina pectoris (SAP) of functional class (FC) II–III, who were assigned into two groups: group 1 comprised 65 patients with left ventricular ejection fraction (LVEF) ≥55 %, and group 2 was composed of 55 patients with LVEF

Abstract Background The effects of air pollution on endothelial function remain unclear across populations. We aimed to use brachial artery flow-mediated dilatation (FMD) to identify demographic differences in the effects of air pollution exposure on endothelial dysfunction. Methods We measured FMD in 850 participants from October 2016 to January 2020. Location-specific concentrations of fine particulate matter

Pulmonary hypertension is a condition characterized by a progressive increase in pressure in the pulmonary circulation. The simplest and most common experimental model of pulmonary hypertension is the monocrotaline model. It is based on the process of transformation of monocrotaline in the liver by cytochrome P450 into endothelial toxic monocrotaline pyrrole, which in turn, damaging the endothelium of the pulmonary vessels, leads to circulatory disorders in the pulmonary circulation and the formation of pulmonary hypertension. Thus, additional prestimulation of cytochrome P450 may increase the stability and representativeness of the monocrotaline model. The purpose of this work was to determine differences in morphological changes in the myocardium and pulmonary vessels of rats in which pulmonary hypertension was modeled using monocrotaline with and without additional stimulation of liver enzymes. Material and methods. The study was conducted on 24 mature male Wistar rats. The animals were divided into 4 groups of 6 rats. Group 1 was represented by intact animals. In groups 2, 3 and 4, modeling of pulmonary hypertension in rats was carried out with a single subcutaneous injection of an aqueous-alcohol solution of monocrotaline at a dose of 60 mg/kg. In order to induce cytochrome P450 in groups 3 and 4, animals were intragastrically administered phenobarbital for one and three days, respectively. Results and discussion. The area of cardiomyocyte nuclei in the groups with one- and three-day preliminary stimulation of liver enzymes was 22.78 ± 3.4 and 23.63 ± 3.72 µm2 , respectively, significantly different from the corresponding values of the control group and group 2. Similar results were revealed when determining the index of the thickness of the medial membrane of small-caliber pulmonary arteries – 58.32 ± 10.02 and 76.44 ± 18.55 % in the groups with one- and three-day preliminary stimulation, respectively. In addition to quantitative changes, qualitative changes were also noted: with additional activation of cytochrome P450, interstitial fibrosis and myocarditis more intensively formed in the myocardium, and signs of “monocrotaline syndrome” more rapidly arose and progressed in the lungs. Conclusions. Based on the data obtained, it can be assumed that preliminary cytochrome P450 causes an increase in the stability, reproducibility and severity of morphological changes in the monocrotaline model of pulmonary hypertension.

Abstract Background SARS-CoV-2 is a systemic disease that affects endothelial function and leads to coagulation disorders, increasing the risk of mortality. Blood levels of endothelial biomarkers such as Von Willebrand Factor (VWF), Thrombomodulin or Blood Dendritic Cell Antigen-3 (BDCA3), and uUokinase (uPA) increase in patients with severe disease and can be prognostic indicators for mortality. Therefore, the aim of this study was to determine the effect of VWF, BDCA3, and uPA levels on mortality. Methods From May 2020 to January 2021, we studied a prospective cohort of hospitalized adult patients with polymerase chain reaction (PCR)-confirmed COVID-19 with a SaO2 ≤ 93% and a PaO2/FiO2 ratio

Abstract Coronary artery bypass surgery can result in endothelial dysfunction due to ischemia/reperfusion (IR) injury. Previous studies have demonstrated that DuraGraft helps maintain endothelial integrity of saphenous vein grafts during ischemic conditions. In this study, we investigated the potential of DuraGraft to mitigate endothelial dysfunction in arterial grafts after IR injury using an aortic transplantation model. Lewis rats (n = 7–9/group) were divided in three groups. Aortic arches from the control group were prepared and rings were immediately placed in organ baths, while the aortic arches of IR and IR + DuraGraft rats were preserved in saline or DuraGraft, respectively, for 1 h before being transplanted heterotopically. After 1 h after reperfusion, the grafts were explanted, rings were prepared, and mounted in organ baths. Our results demonstrated that the maximum endothelium-dependent vasorelaxation to acetylcholine was significantly impaired in the IR group compared to the control group, but DuraGraft improved it (control: 89 ± 2%; IR: 24 ± 1%; IR + DuraGraft: 48 ± 1%, p

Abstract Background Uveal melanoma (UM), the most common adult intraocular tumor, is characterized by high malignancy and poor prognosis in advanced stages. Angiogenesis is critical for UM development, however, not only the role of vascular endothelial dysfunction in UM remains unknown, but also their analysis at the single-cell level has been lacking. A comprehensive analysis is essential to clarify the role of the endothelium in the development of UM. Methods By using single-cell RNA transcriptomics data of 11 cases of primary and liver metastasis UM, we analyzed the endothelial cell status. In addition, we analyzed and validated ECs in the in vitro model and collected clinical specimens. Subsequently, we explored the impact of endothelial dysfunction on UM cell migration and explored the mechanisms responsible for the endothelial cell abnormalities and the reasons for their peripheral effects. Results UM metastasis has a significantly higher percentage of vascular endothelial cells compared to in situ tumors, and endothelial cells in metastasis show significant senescence. Senescent endothelial cells in metastatic tumors showed significant Krüppel-like factor 4 (KLF4) upregulation, overexpression of KLF4 in normal endothelial cells induced senescence, and knockdown of KLF4 in senescent endothelium inhibited senescence, suggesting that KLF4 is a driver gene for endothelial senescence. KLF4-induced endothelial senescence drove tumor cell migration through a senescence-associated secretory phenotype (SASP), of which the most important component of the effector was CXCL12 (C-X-C motif chemokine ligand 12), and participated in the composition of the immunosuppressive microenvironment. Conclusion This study provides an undesirable insight of senescent endothelial cells in promoting UM metastasis.

Introduction: Hypertension (HTN) is the third leading risk factor contributing to the disease burden in Southeast Asia. Understanding its underlying mechanism, such as endothelial dysfunction, is very important. Apelin is a recently discovered endogenous peptide hormone that, along with Nitric Oxide (NO), is implicated in endothelial dysfunction and the severity of HTN. This can significantly reduce renal function and lead to microalbuminuria/proteinuria in 5-15% of patients. Aim: To measure serum apelin and NO in patients with newly diagnosed primary HTN with or without microalbuminuria and to investigate the correlation of serum apelin with HTN in the same study population. Materials and Methods: This cross-sectional study was conducted from February 2019 to January 2021 in the Department of Biochemistry In collaboration with the Department of Medicine at SCB Medical College and Hospital, Cuttack, Odisha, India. A total of 180 participants were included in the present study. Among them, 90 were newly diagnosed hypertensive patients, and 90 were non hypertensive. The study comprised of 90 hypertensive patients, with 46 having microalbuminuria (Group-A), 44 without microalbuminuria (Group-B) and 90 normotensive controls (Group-C). All participants underwent evaluation of their biochemical profile which included Fasting Plasma Sugar (FBS), serum urea, creatinine, Total Cholesterol (TC), Triglyceride (TG), High-density Lipoprotein cholesterol (HDL-c), Low-density Lipoprotein cholesterol (LDL-c), Very Low-Density Lipoprotein (VLDL), serum apelin and NO levels, and urine albumin. The comparison between the three groups was done by using Analysis of Variance (ANOVA) test with post-hoc analysis. The Chi-square test was used to compare categorical variables. Results: The mean age of the participants was 50.48±9.73 years. study comprised of 90 hypertensive patients, with 46 having microalbuminuria, 44 without microalbuminuria, and 90 normotensive controls. The mean serum apelin levels were 394.45±84.2, 386.9±86.12, and 62.73±22.87 ng/L, respectively, among patients with microalbuminuria, without microalbuminuria, and normotensive patients. Similarly, the mean serum NO levels were 6.31±2.94, 8.32±2.63, and 20.15±4.37 μmol/L, respectively, among the three groups. The comparison of mean values indicated a significant (p

Endothelial-to-mesenchymal transition (EndMT) is a key driver of atherosclerosis. Aerobic glycolysis is increased in the endothelium of atheroprone areas, accompanied by elevated lactate levels. Histone lactylation, mediated by lactate, can regulate gene expression and participate in disease regulation. However, whether histone lactylation is involved in atherosclerosis remains unknown. Here, we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la) in vitro and in vivo, as well as in atherosclerotic patients’ arteries. Mechanistically, the histone chaperone ASF1A was first identified as a cofactor of P300, which precisely regulated the enrichment of H3K18la at the promoter of SNAI1, thereby activating SNAI1 transcription and promoting EndMT. We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction. Functional analysis based on ApoeKOAsf1aECKO mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endothelium-specific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development. Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis, which provides emerging therapies for atherosclerosis.

Relevance. In the Republic of Tajikistan, in recent years there has been a steady increase in cardiovascular diseases. In this regard, special attention is paid to coronary heart disease with its various manifestations, which can often cause permanent disability, even death. In recent decades, there has been great interest among research scientists in studying the functioning of the endothelium in various forms of coronary heart disease, as well as in individuals with post-infarction cardiosclerosis as a complication of coronary heart disease. Despite the large number of studies in this area, the role and relationship of some sensitive markers of endothelial dysfunction with the clinical course of various forms of coronary heart disease have not yet been determined. That is why its detailed study is of unconditional clinical interest and provides the opportunity for a deep understanding of its theoretical aspects. Purpose of the study: to study risk factors for cardiovascular diseases and mark­ers of endothelial dysfunction in patients with stable angina pectoris in comparison with patients with post-infarction cardiosclerosis, i.e. previous myocardial infarction.Object and methods. Of 60 patients with various forms of coronary heart disease, whose average age was 62.6 ± 3.5 years, and 20 practically healthy individuals of the same age who made up the control group, three groups were formed: Group I (n = 20) included respondents without coronary heart disease; Group II (n = 30) included patients with stable angina pectoris of functional class II and III; Group III (n = 30) included patients who were diagnosed with post-infarction cardiosclerosis, i.e. previously suffered a myocardial infarction. Endothelial cell dysfunction was detected by determining desquamated endothelial cells, as well as by the activity of von Willebrand factor and the level of homocysteine in the blood plasma.Results. In the examined patients, risk factors for coronary heart disease in the form of arterial hypertension, physical inactivity and obesity were observed with greater frequency in persons with stable angina pectoris of functional class II, in contrast to those with functional class III. Patients with stable angina pectoris of functional class III all had chronic heart failure of varying severity (100%). Most patients had at least three risk factors for coronary heart disease. All persons with post-infarction cardiosclerosis had risk factors for coro­nary heart disease, while arterial hypertension was detected in 100%. Based on the indicators of endothelial dysfunction, it can be said that individuals in group III have a more severe functional and morphological condition (increased homocysteine levels, von Willebrand factor activity and the number of desquamated endothelial cells) compared to group II (p < 0.001).Conclusion. In all forms of coronary heart disease (stable exertional angina of functional class II, III and post-infarction cardiosclerosis), the content of desquamated endothelial cells in the blood serum, the activity of von Willebrand factor and homocysteine are increased. A positive correlation was established between the level of desquamated endothelial cells and the level of homocysteine, von Willebrand factor, fibrinogen and platelets. After complex therapy of patients with various forms of coronary heart disease, the functional state of the endothelium improves (decrease in the level of desquamated endothelial cells, ho­mocysteine, von Willebrand factor).

Endothelial dysfunction (ED) serves as the pathological basis for various cardiovascular diseases. Guanosine triphosphate cyclopyrrolone 1 (GCH1) emerges as a pivotal protein in sustaining nitric oxide (NO) production within endothelial cells, yet it undergoes degradation under oxidative stress, contributing to endothelial cell dysfunction. Citronellal (CT), a monoterpenoid, has been shown to ameliorate endothelial dysfunction induced by in atherosclerosis rats. However, whether CT can inhibit the degradation of GCH1 protein is not clear. It has been reported that ubiquitination may play a crucial role in regulating GCH1 protein levels and activities. However, the specific E3 ligase for GCH1 and the molecular mechanism of GCH1 ubiquitination remain unclear. Using data-base exploration analysis, we find that the levels of the E3 ligase Smad-ubiquitination regulatory factor 2 (Smurf2) negatively correlate with those of GCH1 in vascular tissues and HUVECs. We observe that Smurf2 interacts with GCH1 and promotes its degradation via the proteasome pathway. Interestingly, ectopic Smurf2 expression not only decreases GCH1 levels but also reduces cell proliferation and reactive oxygen species (ROS) levels, mostly because of increased GCH1 accumulation. Furthermore, we identify BH 4/eNOS as downstream of GCH1. Taken together, our results indicate that CT can obviously improve vascular endothelial injury in Type 1 diabetes mellitus (T1DM) rats and reverse the expressions of GCH1 and Smurf2 proteins in aorta of T1DM rats. Smurf2 promotes ubiquitination and degradation of GCH1 through proteasome pathway in HUVECs. We conclude that the Smurf2-GCH1 interaction might represent a potential target for improving endothelial injury.

Abstract Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future.