Endothelial Oxidative Stress Research Articles

Epigenetic DNA Methylation and Protein Homocysteinylation: Key Players in Hypertensive Renovascular Damage

Hypertension has been a threat to the health of people, the mechanism of which, however, remains poorly understood. It is clinically related to loss of nephron function, glomerular sclerosis, or necrosis, resulting in renal functional declines. The mechanisms underlying hypertension’s development and progression to organ damage, including hypertensive renal damage, remain to be fully elucidated. As a developing approach, epigenetics has been postulated to elucidate the phenomena that otherwise cannot be explained by genetic studies. The main epigenetic hallmarks, such as DNA methylation, histone acetylation, deacetylation, noncoding RNAs, and protein N-homocysteinylation have been linked with hypertension. In addition to contributing to endothelial dysfunction and oxidative stress, biologically active gases, including NO, CO, and H2S, are crucial regulators contributing to vascular remodeling since their complex interplay conducts homeostatic functions in the renovascular system. Importantly, epigenetic modifications also directly contribute to the pathogenesis of kidney damage via protein N-homocysteinylation. Hence, epigenetic modulation to intervene in renovascular damage is a potential therapeutic approach to treat renal disease and dysfunction. This review illustrates some of the epigenetic hallmarks and their mediators, which have the ability to diminish the injury triggered by hypertension and renal disease. In the end, we provide potential therapeutic possibilities to treat renovascular diseases in hypertension.

The prothrombotic state in patients with type 2 diabetes mellitus and ischemic heart failure: an association with endothelial dysfunction

Abstract Background Heart failure (HF) is associated with a substantial prothrombotic state and an increased risk of thromboembolism, regardless of the presence of atrial fibrillation (AF). Although oral anticoagulation in HF with known AF is recommended, there is no conclusive evidence supporting clinical benefits of chronic anticoagulation in HF subjects without AF. Other factors enhancing prothrombotic state, often concomitant with HF, are type 2 diabetes mellitus (T2D) and coronary artery disease (CAD). T2D as well as CAD are independently associated with a hypercoaguability due to multiple mechanisms including endothelial dysfunction and oxidative stress. Dysfunction of endothelium was observed in patients with HF, however a little is known about its influence on prothrombotic state in a very high risk HF population. Purpose This study aimed to investigate whether the prothrombotic state in patients with T2D, CAD, and HF, depends on the left ventricular ejection fraction (LVEF) or endothelial function. Methods We assessed 54 patients with stable chronic HF, CAD, and T2D. Based on the echocardiography examination 28 of them were those with HF with reduced ejection fraction (HFrEF) and 26 of them were classified as HF with preserved ejection fraction (HFpEF) according to current guidelines. Fibrin clot density reflected by clot permeability (Ks) and thrombin generation were evaluated. Endothelial function was determined in flow-mediated (FMD) and nitroglycerin-mediated dilatation (NMD) tests of the brachial artery. Results Subjects in both groups were comparable in terms of cardiovascular risk factors except for lower glomerular filtration rate (GFR) by 18.1%. HFrEF patients had lower Ks by 20.3%, along with higher endogenous thrombin potential (ETP) by 18.9% and maximum thrombin level (Peak) by 24.1% as compared with HFpEF. While there were no differences in FMD and NMD between subjects, we found negative correlations of NMD with ETP and Peak (r=-0.448, P=0.001; r=-0.304, P=0.034, respectively). Moreover, the proportion of NMD and FMD along with GFR and LVEF were also significantly associated with both thrombogram parameters (<0.01 for all). By the multivariate analysis of the whole population, NMD, LVEF, low-density lipoprotein and GFR were independent predictors of ETP (R2=0.530, P<0.001) while NMD, LVEF, and GFR predicted Peak levels (R2=0.327, P=0.002). Conclusion We showed for the first time that patients with ischemic etiology of HFrEF and T2D presented altered fibrin clot properties and enhanced thrombin generation compared to HFpEF subjects. It might be hypothesized that endothelial dysfunction induced by T2D could intensify hypercoagulability in patients with HF.Figurę 1

Enzyme Activity-Based Optical Probe: Imaging Aminopeptidases N in Vulnerable Plaque and Serum.

Cardiovascular disease, a chronic and progressive arterial wall disease, is increasingly recognized for its clinical significance. Aminopeptidases N (APN), crucial in the pathophysiological processes of vulnerable plaque, have been linked to endothelial dysfunction, oxidative stress, and plaque formation, thus highlighting their potential as biomarkers for disease progression. However, current detection methods for APN in body fluids and in vivo have limitations, including insufficient sensitivity and specificity, time delays, and the inability to directly reflect enzyme activity in plaques. To address these challenges, we developed an optical probe, HD-APN, for in vivo imaging of aminopeptidases, providing a potential implementation in cardiovascular disease. Our work demonstrated the applicability of HD-APN for specific monitoring of aminopeptidase levels in plaques and serum, shedding light on its potential for further research in cardiovascular disease.

Vascular inflammaging: Endothelial CEACAM1 expression is upregulated by TNF-α via independent activation of NF-κB and β-catenin signaling.

Chronic inflammation with progressive age, called inflammaging, contributes to the pathogenesis of cardiovascular diseases. Previously, we have shown increased vascular expression of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in aged mice and humans, presumably via mutual upregulation with the pro-inflammatory cytokine TNF-α. CEACAM1 is critical for aging-associated vascular alterations like endothelial dysfunction, fibrosis, oxidative stress, and sustained inflammation and can be regarded as a main contributor to vascular inflammaging. This study was conducted to elucidate the mechanisms underlying endothelial CEACAM1 upregulation by TNF-α in detail. Using wildtype (WT) and TNF-α knockout (Tnf-/-) mice, we confirmed that the aging-related upregulation of endothelial CEACAM1 critically depends on TNF-α. The underlying mechanisms were analyzed in an endothelial cell culture model. TNF-α time-dependently upregulated CEACAM1 invitro. In pharmacological experiments, we identified an early NF-κB- and a delayed β-catenin-mediated response. Involvement of β-catenin was further substantiated by siRNA-mediated knockdown of the β-catenin-targeted transcription factor TCF4. Both signaling pathways acted independent from each other. Elucidating the delayed response, co-immunoprecipitation analysis revealed release of β-catenin from adherens junctions by TNF-α. Finally, TNF-α activated Akt kinase by increasing its Ser473 phosphorylation. Consequently, Akt kinase facilitated β-catenin signaling by inhibiting its degradation via phosphorylation of GSK3β at Ser9 and by increased phosphorylation of β-catenin at Ser552 that augments its transcriptional activity. Taken together, our study provides novel mechanistic insights into the aging-related, inflammation-mediated endothelial upregulation of CEACAM1. Beyond the pathogenesis of cardiovascular diseases, these findings may be significant to all fields of inflammaging.

Aged Gut Microbiome Induces Metabolic Impairment and Hallmarks of Vascular and Intestinal Aging in Young Mice.

Aging, an independent risk factor for cardiometabolic diseases, refers to a progressive deterioration in physiological function, characterized by 12 established hallmarks. Vascular aging is driven by endothelial dysfunction, telomere dysfunction, oxidative stress, and vascular inflammation. This study investigated whether aged gut microbiome promotes vascular aging and metabolic impairment. Fecal microbiome transfer (FMT) was conducted from aged (>75 weeks old) to young C57BL/6 mice (8 weeks old) for 6 weeks. Wire myography was used to evaluate endothelial function in aortas and mesenteric arteries. ROS levels were measured by dihydroethidium (DHE) staining and lucigenin-enhanced chemiluminescence. Vascular and intestinal telomere function, in terms of relative telomere length, telomerase reverse transcriptase expression and telomerase activity, were measured. Systemic inflammation, endotoxemia and intestinal integrity of mice were assessed. Gut microbiome profiles were studied by 16S rRNA sequencing. Some middle-aged mice (40-42 weeks old) were subjected to chronic metformin treatment and exercise training for 4 weeks to evaluate their anti-aging benefits. Six-week FMT impaired glucose homeostasis and caused vascular dysfunction in aortas and mesenteric arteries in young mice. FMT triggered vascular inflammation and oxidative stress, along with declined telomerase activity and shorter telomere length in aortas. Additionally, FMT impaired intestinal integrity, and triggered AMPK inactivation and telomere dysfunction in intestines, potentially attributed to the altered gut microbial profiles. Metformin treatment and moderate exercise improved integrity, AMPK activation and telomere function in mouse intestines. Our data highlight aged microbiome as a mechanism that accelerates intestinal and vascular aging, suggesting the gut-vascular connection as a potential intervention target against cardiovascular aging and complications.

Association Between NOX2-Mediated Oxidative Stress, Low-Grade Endotoxemia, Hypoalbuminemia, and Clotting Activation in COVID-19.

Low-grade endotoxemia by lipopolysaccharide (LPS) has been detected in COVID-19 and could favor thrombosis via eliciting a pro-inflammatory and pro-coagulant state. The aim of this study was to analyze the mechanism accounting for low-grade endotoxemia and its relationship with oxidative stress and clotting activation thrombosis in COVID-19. We measured serum levels of sNOX2-dp, zonulin, LPS, D-dimer, and albumin in 175 patients with COVID-19, classified as having or not acute respiratory distress syndrome (ARDS), and 50 healthy subjects. Baseline levels of sNOX2-dp, LPS, zonulin, D-dimer, albumin, and hs-CRP were significantly higher in COVID-19 compared to controls. In COVID-19 patients with ARDS, sNOX2-dp, LPS, zonulin, D-dimer, and hs-CRP were significantly higher compared to COVID-19 patients without ARDS. Conversely, concentration of albumin was lower in patients with ARDS compared with those without ARDS and inversely associated with LPS. In the COVID-19 cohort, the number of patients with ARDS progressively increased according to sNOX2-dp and LPS quartiles; a significant correlation between LPS and sNOX2-dp and LPS and D-dimer was detected in COVID-19. In a multivariable logistic regression model, LPS/albumin levels and D-dimer predicted thrombotic events. In COVID-19 patients, LPS is significantly associated with a hypercoagulation state and disease severity. In vitro, LPS can increase endothelial oxidative stress and coagulation biomarkers that were reduced by the treatment with albumin. In conclusion, impaired gut barrier permeability, increased NOX2 activation, and low serum albumin may account for low-grade endotoxemia and may be implicated in thrombotic events in COVID-19.

Integrated metabolomics and network pharmacology to reveal the mechanisms of Shexiang Baoxin pill against atherosclerosis

BackgroundAtherosclerosis is a disease marked by the development of lipid lesions within the endothelium and continues to be a prominent contributor to global mortality. Shexiang Baoxin pill (SBP) has been employed in the management of numerous cardiovascular diseases, but the complex mechanisms by which it operates remain obscure. This research was conducted to determine the potential impact of SBP on atherosclerosis and the underlying regulatory mechanism involved. MethodNetwork pharmacology was utilized to predict the key drug-disease targets, and a nontargeted metabolomic assay was applied to identify the key metabolites and metabolic pathways. A mouse atherosclerosis model was constructed to clarify the protective effect of SBP on atherosclerosis, and in vivo and in vitro tests were performed to verify the analysis results and clarify the mechanism through which SBP affects atherosclerosis. ResultsThe results show that SBP can exert a protective effect in vivo by decreasing lipid levels, plaque formation and endothelial damage. Network pharmacology and metabolomics revealed that MAPK3, AKT1 and STAT3 were the hub targets and that trimethylamine n-oxide (TMAO) was the pivotal metabolite. Due to the atherogenic effect of TMAO, the corresponding protective effect of SBP was investigated in vitro. SBP inhibited TMAO-induced endothelial cell apoptosis and oxidative stress and counteracted the upregulation of MAPK3, AKT1, and STAT3 expression. Molecular docking and enzymatic inhibition suggested that the active components of SBP could bind stably to key target proteins. ConclusionTaken together, based on the integrated metabolomics and network pharmacology, our findings suggest that SBP may be implicated in TMAO-induced atherosclerosis by affecting endothelial function and bile acid synthesis. We observed that SBP may ameliorate atherosclerosis by regulating TMAO levels through multiple pathways, which may provide a novel direction and insight for SBP involved in cardiovascular protection by mediating the gut-heart axis.

12489 Senolytics Dasatinib And Quercetin Alleviate Type 1 Diabetes-Related Cardiac Fibrosis In Male Akita Ins-/+Mice

Abstract Disclosure: N. Kadoumi: None. G. Zatarah: None. J. Stokar: None. P. Shivam: None. I. Gurt: None. R. Dresner-Pollak: None. People living with type 1 diabetes (T1D) have a markedly shorter life expectancy compared to non-diabetic age- and sex-matched controls primarily due to cardiovascular disease. Diabetic cardiomyopathy is characterized by structural and functional alterations that occur independently of hypertension or coronary artery leading to congestive heart failure. The pathogenesis of diabetic cardiomyopathy involves endothelial cell dysfunction, microangiopathy, mitochondrial dysfunction, and oxidative stress, resulting in inflammation, extensive remodeling, cardiomyocyte hypertrophy, interstitial fibrosis, and apoptosis. T1D is associated with accelerated aging. Cellular senescence is a hallmark of aging, it is characterized by cell cycle arrest, distinct morphological alterations and the release of molecules referred to as the senescence-associated secretory phenotype (SASP). Senescent cardiomyocytes secrete SASPs that promote activation of fibroblasts, hypertrophy of cardiac muscle cells, and dysfunction of cardiac endothelial cells. An increase in cardiac cellular senescence was demonstrated in mouse models of T1D. Senolytics are compounds that clear senescent cells. Senolytics were shown to improve multiple outcomes in age-associated conditions in mice and humans.We investigated the effects of senolytics Dasatinib (D) and Quercetin (Q) on cardiac fibrosis in the AKITA Ins-/+ mouse model of T1D.We first assessed if there is increased collagen type1 expression in the heart ventricles and perivascular in 3-month-old in AKITA Ins-/+ vs. WT male mice using Immunofluorescence. Increased perivascular and interstitial expression of collagen 1 was found in AKITA Ins-/+ compared to WT age-and sex-matched mice (0.0811±0.008177 µm2 vs. 0.0533± 0.007960 µm2 ,P=0.0476), (105.7±10.29 µm2 vs. 54.85±14.61 µm2, P=0.0476), respectively. Next, 3-month-old AKITA Ins-/+wmale mice were randomly assigned to treatment with Dasatinib (5 mg/kg) and Quercetin (50 mg/kg) or vehicle administered once monthly by oral gavage for a total of four months (n=20, 10 in each group). Heart samples were analyzed for gene expression, collagen 1 protein by western blotting and Immunofluorescence and analyzed using QuPath 0.5.0 Software. Interstitial and perivascular fibrosis was separately assessed in the right and left ventricles. Treatment with D+Q resulted in a 2-fold decrease in COL1A1 gene and Collagen 1 protein expression by RT-PCR and western blot analysis (P= 0.011 and 0.042, respectively) in AKITA Ins-/+ mice. Immunostaining analysis revealed reduced Collagen 1 deposition in both the left and right ventricles (105.7±10.29 µm2 vs. 43.53±16.31 µm2, P=0.0571), as well as in the perivascular area (0.0811±0.008177 µm2 vs. 0.052±0.006163 µm2, P=0.1143). Treatment with senolytics D+Q reduces the expression of Collagen I, a key factor in myocardial fibrosis, in adult male AKITA Ins-/+ mice. Presentation: 6/3/2024

Diabetes Mellitus and Neurovascular Pathology: A Comprehensive Review of Retinal and Brain Lesions.

Diabetes mellitus (DM) is a chronic metabolic disorder marked by persistent hyperglycemia, which significantly impacts vascular health. This review comprehensively analyzes the neurovascular complications associated with DM, focusing on retinal and brain lesions. Diabetes is categorized into type 1 DM, type 2 DM, and gestational DM, each presenting unique challenges and risks. The condition accelerates vascular damage through mechanisms such as endothelial dysfunction, inflammation, and oxidative stress, leading to severe microvascular complications. Diabetic retinopathy is a primary concern, with its progression from non-proliferative to proliferative stages potentially resulting in vision loss. Concurrently, diabetes contributes to neurovascular damage in the brain, increasing the risk of cognitive decline and cerebrovascular events. This review examines the pathophysiological mechanisms underlying these complications, evaluates current diagnostic and management strategies, and highlights recent advancements in imaging technologies and therapeutic approaches. Integrating these insights is crucial for improving early detection, treatment, and management of diabetes-related neurovascular issues. Future research should focus on innovative preventive measures and therapeutic interventions to mitigate the long-term impact of diabetes on vascular health. By enhancing our understanding of these complex interactions, this review aims to contribute to better clinical practices and improved patient outcomes in diabetes care.

Drivers of cardiovascular disease in metabolic dysfunction-associated steatotic liver disease: the threats of oxidative stress.

Non-alcoholic fatty liver disease (NAFLD), now known as metabolic-associated steatotic liver disease (MASLD), is the most common liver disease worldwide, with a prevalence of 38%. In these patients, cardiovascular disease (CVD) is the number one cause of mortality rather than liver disease. Liver abnormalities per se due to MASLD contribute to risk factors such as dyslipidemia and obesity and increase CVD incidents. In this review we discuss hepatic pathophysiological changes the liver of MASLD leading to cardiovascular risks, including liver sinusoidal endothelial cells, insulin resistance, and oxidative stress with a focus on glutathione metabolism and function. In an era where there is an increasingly robust recognition of what causes CVD, such as the factors included by the American Heart Association in the recently developed PREVENT equation, the inclusion of liver disease may open doors to how we approach treatment for MASLD patients who are at risk of CVD.

Impaired microvascular insulin-dependent dilation in women with a history of gestational diabetes.

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10-10-10-1 M) and insulin (10-8-10-4 M) in control sites and sites treated with 15 mM l-NAME [NG-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine (P = 0.006) and insulin (P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC (P = 0.009) but had no effect in GDM (P = 0.306). Ascorbate treatment increased acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC (P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance.NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

Sinomenine Hydrochloride Regulates the Apoptosis of Endothelial Cells through PPAR-γ to Alleviate PAH.

Pulmonary arterial hypertension is a progressive heart and lung disease that is caused by irreversible pulmonary vascular remodeling. Sinomenine hydrochloride is an alkaloid that is extracted from sinomenium acutum, which has strong anti-inflammatory effects. In this study, male rats were injected with monocrotaline, and endothelial cells were exposed to hypoxia for 24 hours to induce pulmonary arterial hypertension. Apoptosis, inflammation, and oxidative stress pathways were observed the in lungs and cells. Sinomenine hydrochloride repressed the increased right ventricular systolic pressure and attenuated the right ventricular hypertrophy and pulmonary artery remodeling in model rats. It reversed the expression of BCL2 and BAX and prevented the apoptosis of endothelial cells. Additionally, it increased the contents of IKBα and NRF2. P65, P-P65, TNFα, IL1β, and IL6 levels in the lungs decreased by it. Malondialdehyde contents decreased, and the superoxide dismutase and glutathione peroxidase activity and HO-1 level increased in the treatment group. In vivo, it promoted apoptosis of pulmonary artery endothelial cells. Moreover, by activating PPAR-γ, sinomenine hydrochloride attains the above effects. These data suggested that sinomenine hydrochloride could protect endothelial cells, restrain inflammation and oxidative stress, and enhance pulmonary vascular remodeling.

Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target?

Cardiovascular disease is a leading cause of morbidity and mortality. New research elucidates increasingly complex relationships between cardiac and metabolic health, giving rise to new possible therapeutic targets. Sphingolipids are a heterogeneous class of bioactive lipids with critical roles in normal human physiology. They have also been shown to play both protective and deleterious roles in the pathogenesis of cardiovascular disease. Ceramides are implicated in dysregulating insulin signalling, vascular endothelial function, inflammation, oxidative stress, and lipoprotein aggregation, thereby promoting atherosclerosis and vascular disease. Ceramides also advance myocardial disease by enhancing pathological cardiac remodelling and cardiomyocyte death. Glucosylceramides similarly contribute to insulin resistance and vascular inflammation, thus playing a role in atherogenesis and cardiometabolic dysfunction. Sphingosing-1-phosphate, on the other hand, may ameliorate some of the pathological functions of ceramide by protecting endothelial barrier integrity and promoting cell survival. Sphingosine-1-phosphate is, however, implicated in the development of cardiac fibrosis. This review will explore the roles of sphingolipids in vascular, cardiac, and metabolic pathologies and will evaluate the therapeutic potential in targeting sphingolipids with the aim of prevention and reversal of cardiovascular disease in order to improve long-term cardiovascular outcomes.

Magnesium Sulfate, Rosuvastatin, Sildenafil and Their Combination in Chronic Hypoxia-Induced Pulmonary Hypertension in Male Rats.

Previous experimental findings have led to considerable interest in the beneficial effects on pulmonary hypertension (PH) produced by sildenafil and in the pleiotropic effects of rosuvastatin and their positive role in the process of pulmonary angiogenesis. However, magnesium sulfate, the most abundant intracellular cation, is essential in vascular endothelial functionality due to its anti-inflammatory and vasodilatory effects. Therefore, the present study aims to assess these treatment regimens and how they could potentially provide some additional benefits in PH therapy. Fourteen days after chronic-hypoxia PH was induced, rosuvastatin, sildenafil and magnesium sulfate were administered for an additional fourteen days to male Wistar rats. The Fulton Index, right ventricle (RV) anterior wall thickness, RV internal diameter and pulmonary arterial (PA) acceleration time/ejection time were evaluated, and another four biochemical parameters were calculated: brain natriuretic peptide, vascular endothelial growth factor, nitric oxide metabolites and endothelin 1. The present study demonstrates that sildenafil and rosuvastatin have modest effects in reducing RV hypertrophy and RV systolic pressure. The drug combination of sildenafil + rosuvastatin + magnesium sulfate recorded statistically very highly significant results on all parameters; through their positive synergistic effects on vascular endothelial function, oxidative stress and pathological RV remodeling, they attenuated PH in the chronic hypoxia pulmonary hypertension (CHPH) rat model.

Risk Factors Associated with Angiographic Severity of Coronary Artery Disease Based on Serum Uric Acid: A Study in a Tertiary Care Hospital, Chattogram, Bangladesh

Background: Coronary Artery Disease (CAD) is a leading cause of death worldwide, identifying risk factors and severity is crucial for management and prevention. Serum Uric Acid (SUA) has been proposed as a potential marker for the severity of CAD. Elevated SUA levels are associated with endothelial dysfunction, oxidative stress, and inflammation, all of which contribute to the development and progression of atherosclerosis. This study aims to determine the association of risk factors with the severity of CAD using SUA levels. Materials and methods: This was a cross-sectional observational study conducted in the Department of Cardiology at CMCH in Chattogram over one year from October 2020 to September 2021. After case selection demographic data were collected and transthoracic echocardiography was performed on study patients. Results: The study analyzed the association between SUA level and CAD severity in 130 patients undergoing coronary angiography. The mean SUA level was 5.06 mg/dl and was significantly associated with the presence of CAD, number of vessel involvement and severity of CAD assessed by the Gensini score. The mean SUA level in cases with CAD was significantly higher (5.26 ± 1.32 mg/dl) than in cases without CAD (4.22 ± 1.03 mg/dl). Conclusion: This study concluded that demographic variables and risk factors are associated with the severity of CAD. The severity of CAD was higher in elderly and male patients. The study suggests that when assessing the risk in a CAD patient, hyperuricemia should be considered. IAHS Medical Journal Volume 6(2) December 2023; 48-52

Ginsenoside Rh4 prevents endothelial dysfunction as a novel AMPK activator.

The AMP-activated protein kinase (AMPK) signalling pathway is a desirable target for various cardiovascular diseases (CVD), while the involvement of AMPK-mediated specific downstream pathways and effective interventions in hyperlipidaemia-induced endothelial dysfunction remain largely unknown. Herein, we aim to identify an effective AMPK activator and to explore its efficacy and mechanism against endothelial dysfunction. Molecular docking technique was adopted to screen for the potent AMPK activator among 11 most common rare ginsenosides. In vivo, poloxamer 407 (P407) was used to induce acute hyperlipidaemia in C57BL/6J mice. In vitro, palmitic acid (PA) was used to induce lipid toxicity in HAEC cells. We discovered the strongest binding of ginsenoside Rh4 to AMPKα1 and confirmed the action of Rh4 on AMPK activation. Rh4 effectively attenuated hyperlipidaemia-related endothelial injury and oxidative stress both in vivo and in vitro and restored cell viability, mitochondrial membrane potential and mitochondrial oxygen consumption rate in HAEC cells. Mechanistically, Rh4 bound to AMPKα1 and simultaneously up-regulated AKT/eNOS-mediated NO release, promoted PGC-1α-mediated mitochondrial biogenesis and inhibited P38 MAPK/NFκB-mediated inflammatory responses in both P407-treated mice and PA-treated HAEC cells. The AMPK inhibitor Compound C treatment completely abrogated the regulation of Rh4 on the above pathways and weakened the lowering effect of Rh4 on endothelial impairment markers, suggesting that the beneficial effects of Rh4 are AMPK dependent. Rh4 may serve as a novel AMPK activator to protect against hyperlipidaemia-induced endothelial dysfunction, providing new insights into the prevention and treatment of endothelial injury-associated CVD.

Effect of aortic smooth muscle BK channels on mediating chronic intermittent hypoxia-induced vascular dysfunction.

Chronic intermittent hypoxia (CIH) can lead to vascular dysfunction and increase the risk of cardiovascular diseases, cerebrovascular diseases, and arterial diseases. Nevertheless, mechanisms underlying CIH-induced vascular dysfunction remain unclear. Herein, this study analyzed the role of aortic smooth muscle calciumactivated potassium (BK) channels in CIH-induced vascular dysfunction. CIH models were established in rats and rat aortic smooth muscle cells (RASMCs). Hemodynamic parameters such as mean blood pressure (MBP), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were measured in rats, along with an assessment of vascular tone. NO and ET-1 levels were detected in rat serum, and the levels of ET-1, NO, eNOS, p-eNOS, oxidative stress markers (ROS and MDA), and inflammatory factors (IL-6 and TNF-α) were tested in aortic tissues. The Ca2+ concentration in RASMCs was investigated. The activity of BK channels (BKα and BKβ) was evaluated in aortic tissues and RASMCs. SBP, DBP, and MBP were elevated in CIH-treated rats, along with endothelial dysfunction, cellular edema and partial detachment of endothelial cells. BK channel activity was decreased in CIH-treated rats and RASMCs. BK channel activation increased eNOS, p-eNOS, and NO levels while lowering ET-1, ROS, MDA, IL-6, and TNF-α levels in CIH-treated rats. Ca2+ concentration increased in RASMCs following CIH modeling, which was reversed by BK channel activation. BK channel inhibitor (Iberiotoxin) exacerbated CIH-induced vascular disorders and endothelial dysfunction. BK channel activation promoted vasorelaxation while suppressing vascular endothelial dysfunction, inflammation, and oxidative stress, thereby indirectly improving CIH-induced vascular dysfunction.

Neuromodulation of Cardiovascular Risks Associated With Cardiotoxic Chemotherapy: A First-in-Human Randomized Pilot Study. Neuromodulation in Cancer Study (NCAN).

Cardiotoxic chemotherapy is used to treat malignancies such as breast cancer and lymphoma. These treatments predispose patients to cardiotoxicity that can lead to cancer treatment-related cardiac dysfunction (CTRCD). The use of high doses of anthracyclines or in combination with human epidermal growth factor receptor 2 antagonists is associated with a progressively higher risk of CTRCD. CTRCD is preceded by increased activation of the sympathetic nervous system and abnormal left ventricular mechanical deformation as measured by abnormal global longitudinal strain (GLS). Low-level tragus stimulation (LLTS) is a new, safe, noninvasive technique that offers great potential to reduce increased sympathetic activation and improve GLS. Here, we describe a study method to examine the effects of LLTS on autonomic balance and cardiac function in breast cancer or lymphoma patients treated with anthracyclines. A first-in-human pilot, randomized, double-blind feasibility study will evaluate 104 patients (age >50y) with breast cancer or lymphoma who receive anthracyclines with one additional CTRCD risk factor. Patients undergo 2 weeks of LLTS daily (1 h/d). Autonomic balance will be measured using heart rate variability metrics. Strain imaging using GLS will be performed pre and post-LLTS. Endothelial inflammation and oxidative stress measures will be performed using in vitro assays at baseline and after 2 weeks. We hypothesize that LLTS stabilizes sympathovagal imbalance and improves cardiac performance in anthracycline-treated patients with breast cancer or lymphoma.

Persistent Post COVID-19 Endothelial Dysfunction and Oxidative Stress in Women.

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.

Phytovesicular Nanoconstructs For Advanced Delivery of Medicinal Metabolites: An In-Depth Review.

Phytochemicals, the bioactive compounds in plants, possess therapeutic benefits, such as antimicrobial, antioxidant, and pharmacological activities. However, their clinical use is often hindered by poor bioavailability and stability. Phytosome technology enhances the absorption and efficacy of these compounds by integrating vesicular systems like liposomes, niosomes, transfersomes, and ethosomes. Phytosomes offer diverse biological benefits, including cardiovascular protection through improved endothelial function and oxidative stress reduction. They enhance cognitive function and protect against neurodegenerative diseases in the nervous system, aid digestion and reduce inflammation in the gastrointestinal system, and provide hepatoprotective effects by enhancing liver detoxification and protection against toxins. In the genitourinary system, phytosomes improve renal function and exhibit anti-inflammatory properties. They also modulate the immune system by enhancing immune responses and reducing inflammation and oxidative stress. Additionally, phytosomes promote skin health by protecting against UV radiation and improving hydration and elasticity. Recent patented phytosome technologies have led to innovative formulations that improve the stability, bioavailability, and therapeutic efficacy of phytochemicals, although commercialization challenges like manufacturing scalability and regulatory hurdles remain. Secondary metabolites from natural products are classified into primary and secondary metabolites, with a significant focus on terpenoids, phenolic compounds, and nitrogen-containing compounds. These metabolites have notable biological activities: antimicrobial, antioxidant, antibiotic, antiviral, anti-inflammatory, and anticancer effects. In summary, this review amalgamates the latest advancements in phytosome technology and secondary metabolite research, presenting a holistic view of their potential to advance therapeutic interventions and contribute to the ever-evolving landscape of natural product-based medicine.