Protection Of Vascular Endothelial Cells Research Articles

The association between serum 25-hydroxyvitamin D levels and erectile dysfunction: a two-sample Mendelian randomization analysis.

Considering that vascular endothelial cell dysfunction is the pathological basis of erectile dysfunction (ED), and recognizing the beneficial effects of 25-hydroxyvitamin D (25(OH)D) on vascular endothelial cell protection, the researchers diligently investigated the causal relationship between serum 25(OH)D levels and ED. However, inconsistent clinical evidence has left the association between serum 25(OH)D levels and ED unclear. The objective of this work was to employ Mendelian randomization (MR) analysis to ascertain the potential causal relationship between serum 25(OH)D levels and ED. We conducted a two-sample MR analysis utilizing data from publicly available genome-wide association studies (GWASs). The primary analysis method for the MR analysis was the inverse-variance weighted (IVW) method, supplemented by the MR-Egger and weighted median methods. In addition, we evaluated heterogeneity with Cochran's Q test, assessed pleiotropy using the MR-Egger intercept test, and performed a leave-one-out analysis to identify single-nucleotide polymorphisms (SNPs) with potential effects. Outliers were detected using MR-pleiotropy residual sum and outlier (MR-PRESSO). Genetically predicted serum 25(OH)D levels were not found to be causally associated with ED in IVW method (OR = 1.028, 95% CI = 0.845-1.250, P = 0.785), MR-Egger method (OR = 1.057, 95% CI = 0.782-1.430, P = 0.720), and weighted median method (OR = 1.225, 95% CI = 0.920-1.633, P = 0.165). The results of sensitivity analyses reinforced our conclusion, indicating no evidence of heterogeneity or directional pleiotropy. In summary, our findings do not substantiate a genetic-level causal link between serum 25(OH)D levels and the prevalence of ED. Nonetheless, future research, including larger MR studies, clinical trials, and additional observational studies, is essential to validate and reinforce the outcomes of our present study.

Shear Stress and the AMP-Activated Protein Kinase Independently Protect the Vascular Endothelium from Palmitate Lipotoxicity.

Saturated free fatty acids are thought to play a critical role in metabolic disorders associated with obesity, insulin resistance, type 2 diabetes (T2D), and their vascular complications via effects on the vascular endothelium. The most abundant saturated free fatty acid, palmitate, exerts lipotoxic effects on the vascular endothelium, eventually leading to cell death. Shear stress activates the endothelial AMP-activated protein kinase (AMPK), a cellular energy sensor, and protects endothelial cells from lipotoxicity, however their relationship is uncertain. Here, we used isoform-specific shRNA-mediated silencing of AMPK to explore its involvement in the long-term protection of macrovascular human umbilical vein endothelial cells (HUVECs) against palmitate lipotoxicity and to relate it to the effects of shear stress. We demonstrated that it is the α1 catalytic subunit of AMPK that is critical for HUVEC protection under static conditions, whereas AMPK-α2 autocompensated a substantial loss of AMPK-α1, but failed to protect the cells from palmitate. Shear stress equally protected the wild type HUVECs and those lacking either α1, or α2, or both AMPK-α isoforms; however, the protective effect of AMPK reappeared after returning to static conditions. Moreover, in human adipose microvascular endothelial cells isolated from obese diabetic individuals, shear stress was a strong protector from palmitate lipotoxicity, thus highlighting the importance of circulation that is often obstructed in obesity/T2D. Altogether, these results indicate that AMPK is important for vascular endothelial cell protection against lipotoxicity in the static environment, however it may be dispensable for persistent and more effective protection exerted by shear stress.

Serum-based metabolomics reveals the mechanism of action of isorhynchophylline in the intervention of atherosclerosis in ApoE-/- mice.

Atherosclerosis (AS) is a chronic inflammatory disease with disorders of lipid metabolism. Metabolic disorders, inflammation and lipid deposition are prominent pathological features of atherosclerosis. Isorhynchophylline (IRN) has pharmacological effects such as protection of vascular endothelial cells, anti-inflammatory, anti-thrombotic, and anti-smooth muscle cell proliferation. However, it is unclear whether IRN is efficacious in atherosclerosis. In the present study, we verified the pharmacological efficacy and hepatoprotective effects of IRN in intervening in AS. LC-MS-based serum untargeted metabolomics was performed to search for potential biomarkers and related pathways in IRN-treated AS in ApoE-/- mice. Fifty-eight biomarkers were metabolically disturbed in the model mice compared to controls. Thirteen biomarkers showed optimal recovery methods after IRN-40 mg ml-1 intervention. We identified three metabolic pathways involved in IRN: glycerophospholipid metabolism, linoleic acid metabolism, and alpha-linolenic acid metabolism. These findings provide a research basis for the intervention of IRN in atherosclerosis.

Allii Macrostemonis Bulbus: A Comprehensive Review of Ethnopharmacology, Phytochemistry and Pharmacology.

The dried bulbs of Allii Macrostemonis Bulbus (AMB) are called "" in China and are mainly distributed in Asia. The plant species included in the 2020 Edition of the Chinese Pharmacopoeia (ChP) are Allium macrostemon Bunge (called xiaogensuan in Chinese, A. macrostemon) and Allium chinense G. Don (called xie in Chinese, A. chinense), respectively. In the traditional Chinese medicine (TCM) theoretical system, AMB is warm in nature, acrid-bitter taste, and attributive to the heart, lung, stomach, large intestine meridian. AMB has the function of activating Yang and removing stasis, regulating Qi and eliminating stagnation. Modern pharmacological studies have shown that AMB has anti-platelet aggregation, hypolipidemic, anti-atherosclerotic, cardiomyocyte, vascular endothelial cell protection, anti-cancer, anti-bacterial, anti-asthmatic, and anti-oxidant effects. In some Asian countries, AMB is often used to treat coronary heart disease (CHD), angina pectoris (AP), asthma, and diarrhea. This review collates the botanical background, ethnopharmacology, phytochemistry, pharmacological activities, quality control, and toxicological studies of AMB, and provides an outlook on the current research deficiencies and future research priorities of AMB, intending to provide ideas for future research directions and commercial development.

Activation of Nrf2/HO-1 signaling: An important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress

IntroductionRecently, Nrf2/HO-1 has received extensive attention as the main regulatory pathway of intracellular defense against oxidative stress and is considered an ideal target for alleviating endothelial cell (EC) injury. ObjectivesThis paper aimed to summarized the natural monomers/extracts that potentially exert protective effects against oxidative stress in ECs. MethodsA literature search was carried out regarding our topic with the keywords of “atherosclerosis” or “Nrf2/HO-1” or “vascular endothelial cells” or “oxidative stress” or “Herbal medicine” or “natural products” or “natural extracts” or “natural compounds” or “traditional Chinese medicines” based on classic books of herbal medicine and scientific databases including Pubmed, SciFinder, Scopus, the Web of Science, GoogleScholar, BaiduScholar, and others. Then, we analyzed the possible molecular mechanisms for different types of natural compounds in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. In addition, perspectives for possible future studies are discussed. ResultsThese agents with protective effects against oxidative stress in ECs mainly include phenylpropanoids, flavonoids, terpenoids, and alkaloids. Most of these agents alleviate cell apoptosis in ECs due to oxidative stress, and the mechanisms are related to Nrf2/HO-1 signaling activation. However, despite continued progress in research on various aspects of natural agents exerting protective effects against EC injury by activating Nrf2/HO-1 signaling, the development of new drugs for the treatment of atherosclerosis (AS) and other CVDs based on these agents will require more detailed preclinical and clinical studies. ConclusionOur present paper provides updated information of natural agents with protective activities on ECs against oxidative stress by activating Nrf2/HO-1. We hope this review will provide some directions for the further development of novel candidate drugs from natural agents for the treatment of AS and other CVDs.

Serpins as important protective factors in the pathogenesis of acute lung injury/acute respiratory distress syndrome

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common respiratory disease in clinic, and with a pathological manifestation of pulmonary edema, decreased pulmonary compliance as well as pulmonary epithelial/endothelial cells injury. At present, it was suggested that systemic inflammatory response syndrome (SIRS) caused by various causes which play an important role in the occurrence and development of ALI/ARDS. Widely activated neutrophils can migrate to lung tissue and release plenty of proteases in the procedure of SIRS, including neutrophil serine proteases (NSPs), lysozyme, myeloperoxidase and collagenase, which can induce severe lung injury. Meanwhile, NSPs, such as neutrophil elastase (NE), cathepsin G (CG), proteinase 3 (PR3) and neutrophil serine proteinase 4 (NSP4), are important in the pathogenesis of ALI/ARDS. Therefore, Serpins may protect lung tissue by inhibiting NSPs. However, the specific mechanism of Serpins is not totally clear. In this article, we will discuss the mechanism of action of NSPs in the inflammatory response of ALI/ARDS, the structural overview of Serpins, the primary role of Serpins in ALI/ARDS, such as the inhibition of NSPs activity, other roles of Serpins in ALI/ARDS, such as the inhibition of inflammatory factor release, regulation of apoptosis and protection of vascular endothelial cells and pulmonary surfactant-associated glycoprotein D (SP-D), and the clinical application of exogenous Serpins in ALI/ARDS to explore the role of Serpins in the pathogenesis of ALI/ARDS. The aim is to provide new ideas and strategies for the clinical treatment of ALI/ARDS.

Mechanism prediction of Simiao Yongan Decoction in treatment of psoriasis arthritis based on network pharmacology

To explore the main target and signal pathway of Simiao Yongan Decoction in the treatment of psoriatic arthritis(PsA) by network pharmacology, so as to reveal the intervention mechanism of Simiao Yongan Decoction in the treatment of psoriatic arthritis. The platform of pharmacology technology of traditional Chinese medicine system(TCMSP) was used to predict and screen the active ingredients of Simiao Yongan Decoction, and GeneCards database was searched to obtain the disease target related to the psoriatic arthritis. Protein interaction network model was constructed with STRING platform; drug-component-target-disease network map was constructed with Cytoscape Software; Wayne Diagram of common target of Simiao Yongan Decoction and psoriasis arthritis was drawn with the help of ClusterProfiler R Software. At the same time, the genetic ontology(GO) enrichment analysis and the Kyoto encyclopedia of genes and genomes(KEGG) pathway analysis were conducted. Through database analysis, 1 128 targets related to 70 main active components of Simiao Yongan Decoction and psoriatic arthritis were selected. On this basis, the interaction network between Simiao Yongan Decoction and psoriatic arthritis was constructed, and 38 common targets were screened out. By GO and KEGG enrichment analysis, 135 signal pathways related to the main components of Simiao Yongan Decoction were selected. It was found that Simiao Yong-an Decoction may play a role in the treatment of psoriatic arthritis through antiviral effect, anti-inflammatory repair, protection of vascular endothelial cells, regulation of immunity and other multiple targets. The mechanism of Simiao Yongan Decoction in the treatment of psoriatic arthritis from multi-component, multi-target and multi-pathway was revealed, which provided a research direction for screening its subsequent clinical effect evaluation indexes.

Consensus of Chinese experts on early prevention and blocking of sepsis

Sepsis is an ongoing conundrum and challenge in medical field. With the rapid development and progress of modern medicine, sepsis has been researched and explored in greater depth across different fields. Although "Surviving Sepsis Campaign" (SSC) has been taken to tackle sepsis in the world for years, its incidence and mortality stay high. According to the updated definition of sepsis stated in the current international guidelines, sepsis is defined as the infection-induced host response disorder, which further results in circulation and/or organ dysfunction. The original source of sepsis is infection, and it is a complicated pathophysiological process from infection to sepsis, which involves the invasion of pathogens, release of cytokines, capillary leakage, and microcirculation dysfunction, thus causing organ metabolism disorder and failure. As shown in Sepsis-3, the sepsis diagnosis standard is stipulated as infection plus sequential organ failure assessment (SOFA) score ≥ 2, and the tackling of sepsis mainly lies on the "life-saving" treatment regarding organ functions. After about 20 years' efforts, SSC has not achieved satisfactory results. As a frontier discipline of acute and critical diseases, emergency medical department is able to receive and cure the patients with acute infection at the earliest. The incidence and mortality of sepsis could be greatly reduced if the possibility of sepsis can be predicted from population characteristics, pathogens and locations of infection, and severity of illness at the early stage of infection. Besides, timely discovering "inflammation storm" by cytokine detection and accessing the patients with an effective clinical scoring system should also be helpful to take more active and effective treatment to the high-risk patients, and block the progression from infection to sepsis. On such a basis, Chinese emergency medicine specialists have put forward the concept of "prevention and blocking" of sepsis, and carried out "Preventing Sepsis Campaign in China" (PSCC) throughout China. They have also proposed the principles of performing targeted diagnosis, examination and treatment at the "early stage of sepsis" and "peri-sepsis period", so as to realize the early prevention, early discovery, and early intervention, and reduce the morbidity and mortality of sepsis, thus providing a new concept for diagnosis and treatment of patients with acute severe infection. This consensus is jointly advocated, discussed and written by four academic societies (associations) and five related publishing houses, and formed after several turns of discussions by more than 40 specialists and experts from emergency medicine, critical medicine, infectious medicine, pharmacy, laboratory medicine, and other professional disciplines. This consensus involves determination and recognition of patients with acute infection, anti-infective therapy, screening of high-risk sepsis patients, discovery of and response to "inflammation storm", protection of vascular endothelial cells and regulation of coagulation function, liquid support scheme and organ function protection strategy, etc. This consensus summarizes the commonly used Western medical diagnosis and treatment measures, and also integrates the advantages of traditional Chinese medicine in prevention and treatment of sepsis, so as to provide a comprehensive reference for the clinicians to perform diagnosis and treatment, and provide a reliable basis for reducing progression of infected patients to sepsis.

Chinese expert consensus on early prevention and intervention of sepsis

Sepsis is currently a major problem and challenge facing the medical community. With rapid development and progress of modern medicine, researchers have put more and more attention on sepsis; meanwhile, the morbidity and mortality of sepsis remains high despite great efforts from experts in various fields. According to updated guidelines, sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Infection is the initial step of sepsis progression, and development from infection to sepsis is a complex pathophysiological process, including pathogen invasion, cytokine release, capillary leakage, microcirculation dysfunction, etc. which finally leads to organ metabolic disorders and functional failure. According to the latest recommended international guidelines of Sepsis 3.0, the presence of infection and SOFA score ≥ 2 are considered as the diagnostic criteria for sepsis, and the “rescue” measures mainly focus on reversal of organ dysfunction. However, despite nearly two decades of efforts, the “Save Sepsis Campaign” has not achieved satisfactory results. Emergency medicine is the frontier subject of acute and severe illness which treats patients with acute infections at the earliest. If at this stage, physicians can predict the possibility of sepsis progression from demographic characteristics, localize the pathogen and infection, detect the inflammatory storms by tests of cytokines and evaluate the severity of the infection with more effective clinical scoring system, and then take effective measures to prevent infection from developing into sepsis in high-risk patients, the morbidity and mortality of sepsis in patients with acute infection will be greatly reduced. Based on this situation, Chinese emergency medicine experts proposed the concept of “preventing and blocking” sepsis, and launched the nationwide “Preventing Sepsis Campaign in China (PSCC)” nationwide. The main concept is summarized as “three early and two reduces” which includes early detection, early diagnosis and early intervention during the “pre-symptomatic” and “peri-septic” stage in order to reduce the incidence of sepsis and it proposed a new approach for diagnosis and treatment of acute severe infection. This consensus is jointly advocated, discussed and written by four academic associations in the field of emergency medicine and five scholarly publishing organizations. More than 40 experts from fields of emergency medicine, critical care medicine, infectious diseases, pharmacy and laboratory medicine have participated in several rounds of deliberation and finally reached consensus on the criteria of identifying patients with acute infection, taking anti-infective treatments, screening of high-risk patients with sepsis, detection and treatment of inflammatory storm, protection of vascular endothelial cells and the regulation of coagulation function, as well as strategies of liquid support and organ function protection etc. The consensus summarizes the commonly used clinical diagnosis criteria and treatment measures of sepsis both in Western medicine and traditional Chinese medicine for clinicians in order to provide evidence for the diagnosis and treatment of the disease.

Protective Effects and Mechanisms of Vaccarin on Vascular Endothelial Dysfunction in Diabetic Angiopathy.

Cardiovascular complications are a major leading cause of mortality in patients suffering from type 2 diabetes mellitus (T2DM). Vascular endothelial dysfunction is a core pathophysiological event in the early stage of T2DM and eventually leads to cardiovascular disease. Vaccarin (VAC), an active flavonoid glycoside extracted from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protection effects. However, little is known about whether VAC is involved in endothelial dysfunction regulation under high glucose (HG) or hyperglycemia conditions. Here, in an in vivo study, we found that VAC attenuated increased blood glucose, increased glucose and insulin tolerance, relieved the disorder of lipid metabolism and oxidative stress, and improved endothelium-dependent vasorelaxation in STZ/HFD-induced T2DM mice. Furthermore, in cultured human microvascular endothelial cell-1 (HMEC-1) cells, we showed that pretreatment with VAC dose-dependently increased nitric oxide (NO) generation and the phosphorylation of eNOS under HG conditions. Mechanistically, VAC-treated HMEC-1 cells exhibited higher AMPK phosphorylation, which was attenuated by HG stimulation. Moreover, HG-triggered miRNA-34a upregulation was inhibited by VAC pretreatment, which is in accordance with pretreatment with AMPK inhibitor compound C (CC). In addition, both reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) and VAC abolished HG-evoked dephosphorylation of AMPK and eNOS, increased miRNA-34a expression, and decreased NO production. These results suggest that VAC impedes HG-induced endothelial dysfunction via inhibition of the ROS/AMPK/miRNA-34a/eNOS signaling cascade.

Levosimendan as a new force in the treatment of sepsis-induced cardiomyopathy: mechanism and clinical application.

The heart is one of the organs most vulnerable to sepsis. This review describes the general characteristics of sepsis-induced cardiomyopathy and the main pathogenesis of myocardial dysfunction in sepsis. Levosimendan is a novel drug for treatment of sepsis-induced myocardial dysfunction. This review also elaborates on the pathogenesis of levosimendan, including the mechanisms of its anti-inflammatory effects, improvement of myocardial ischaemia, increased synthesis of nitric oxide, vascular endothelial cell protection, increased myocardial contractility, improved diastolic function, and inhibition of hypoxia-inducible factor-1α expression. Many clinical studies have proven that levosimendan effectively prevents myocardial dysfunction in sepsis. In addition to the widespread use of levosimendan in patients with heart failure, the role of levosimendan in the treatment of patients with sepsis-induced cardiomyopathy will be increasingly studied and applied in the future.

Propofol activates autophagic activity of vascular endothelial cells by inhibiting SENP1 expression and attenuates vascular endothelial injury induced by ischemia-reperfusion in orthopedic surgery

The aim of this study was to examine the effect and mechanism of SENP1 in the protection of vascular endothelial cells by propofol during ischemia-reperfusion (IR) injury. Thirty-eight patients undergoing minor lower limb orthopedic surgery under general anesthesia were included, and divided evenly into sevoflurane group and propofol group. Peripheral blood was collected before fixing tourniquets (T0 time point) and one hour after releasing tourniquets (T1 time point). Contents of endothelin, vWF and malondialdehyde were determined by enzyme-linked immunosorbent assay to evaluate vascular injury. Quantitative real-time polymerase chain reaction was used to determine mRNA expression; western blotting, to determine protein expression; CCK-8 assay, Transwell assay and flow cytometry, to examine the proliferation, migration and apoptosis of human umbilical vein endothelial cells (HUVECs); western blotting and laser scanning confocal microscopy, to analyze autophagy of HUVECs; protein immunoprecipitation, to examine the relationship between SENP1 and the SUMOylation of autophagy-associated VPS34 protein. The results showed that the contents of peripheral blood vessel injury markers and the expression of SENP1 were elevated when vascular injury was induced by IR in patients undergoing orthopedic surgery, whereas propofol reduced these levels. Inhibition of SENP1 expression reduced injury of HUVECs induced by IR. Silencing expression of SENP1 promoted autophagy of HUVECs. SENP1 promoted deSUMOylation of VPS34, leading to reduced autophagy of HUVECs. The study demonstrates that propofol activates autophagic activity of HUVECs by inhibiting SENP1 expression and attenuates vascular endothelial injury induced by IR in orthopedic surgery. This effect may be related to SENP1 regulating the deSUMOylation of VPS34.

Quercetin Inhibits the Formation of Atherosclerosis Plaque by Protecting Vascular Endothelial Cells

Background: Quercetin and its derivatives are the most widely distributed flavonoids, which have many pharmacological activities, such as anti-oxidation, anti-aging and anti-inflammatory, Quercetin inhibits the occurrence of atherosclerosis (AS) due to its antioxidant activity, but the mechanism is unknown. Results: Our research found that quercetin plays a role in reducing the formation of atherosclerotic plaque by protecting vascular endothelial cell injury. In an atherosclerotic mouse model, quercetin inhibited the formation of atherosclerotic plaques and downregulated the level of endothelial cell protein C receptors (EPCR), thrombomodulin (TM), von willabrand factor (vWF) and intercellular cell adhesion molecule-1(ICAM-1) in peripheral blood of AS mouse, because of increasing the number of vascular endothelial cells at the atherosclerotic plaque. In vitro model of human vascular endothelial cells (HUVECs) injury by H2O2, we found that quercetin significantly reduced endothelial cell apoptosis, and it can prevent vascular endothelial cell injury by inhibiting the secretion of chemokines (CXCL1 and CXCL8) and inflammatory (TNF-α, IL-β, IL-6 and IL-12) factors and reducing macrophage infiltration, at the same time, quercetin promotes the secretion of pro-angiogenic chemokines (CXCL4 and CXCL10) from vascular endothelial cells. Real-time PCR and western-blot assay found that the quercetin protects vascular endothelial cells by inhibiting apoptotic signaling pathway proteins (Bax and Bcl-2) and inflammatory regulatory pathway proteins (IκBα and p65). Conclusion: Consequently, we concluded that the role of quercetin in the protection of vascular endothelial cells against atherosclerotic plaques may be through the inhibition of vascular endothelial cell apoptosis.

SUMO2/3 participates in regulating the protective effect of propofol on human umbilical vein endothelial cells

The present study investigated the role and mechanism of SUMO2/3 in the protection of vascular endothelial cells by propofol. An ischemia-reperfusion (I/R) injury model of human umbilical vein endothelial cells (HUVECs) was constructed. After treatment with propofol, we determined the expression of SUMO2/3 proteins by Western blotting, cell proliferation by CCK-8 assay, cell migration by Transwell assay and apoptosis by flow cytometry. After interference of SUMO2/3, the biological functions of HUVECs were observed. Using Western blotting and laser scanning confocal microscopy, the autophagy of HUVECs was examined. Using immunoprecipitation, the SUMO modification site of Beclin1 was examined. The results showed that I/R injury decreased the proliferation and migration and promoted the apoptosis of HUVECs, and propofol restored the normal biological functions to HUVECs. I/R injury inhibited the expression of SUMO2/3 in HUVECs, and propofol increased the expression of SUMO2/3 in HUVECs. Interference of SUMO2/3 expression suppressed the proliferation and migration, and promoted the apoptosis of HUVECs. Propofol exerted its protective effect on HUVECs via autophagy mediated by SUMO2/3 proteins. Beclin1 was modified by SUMO2/3 at the K26 site. SUMO modification of the K26 site in Beclin1 was involved in the regulation of autophagy of HUVECs, and K26R Beclin1 had reduced effect in activating autophagy of HUVECs compared with wild-type Beclin1. These results demonstrate that SUMO2/3 participates in regulating the protective effect of propofol on HUVECs. SUMO2/3 activates the autophagy activity of cells by modifying the K26 site of Beclin1, thus inhibiting I/R injury to vascular endothelial cells.

P-201 - Prevention of endothelial dysfunction via cross-talk between Nrf2/ARE and IKK/NF-κB pathways by wine pomace product

The hyperglycemia-induced endothelial cell dysfunction is a key event in the onset and progression of cardiovascular disease (CVD), protection of vascular endothelial cells represents an important strategy for the diagnosis of CVD. Previous studies suggest that the polyphenols of a wine pomace (WP) could be able to modulate endothelial dysfunction, increase the levels of nitric oxide and decrease the levels of ROS. The objective of this study was to elucidate some of the possible pathways involved in the potential protective effects against endothelial dysfunction and oxidative damage in the vasculature of WP product. For this, we evaluated the Nrf2/ARE and IKK/IκB/NF-κB pathway in high glucose-induced oxidative stress in the endothelial cell line HUVECs EA.hy926. Analysis revealed that WP product-mediated antioxidant effects were due to up-regulation of cellular anti-oxidant genes, such as HO-1 and NQO-1 via promotion of the transcriptional activity of Nrf2 and down-regulation of the NF-κB pathway. These results suggest that WP product may represent a promising intervention in diabetic-associated cardiovascular diseases by activating the Nrf2-dependent cellular anti-oxidant defense system.

Abstract 216: Hdac2 Modulates Atherosclerosis

Objective: We recently described a novel regulatory role for histone deacetylase 2 (HDAC2) in vascular endothelial cell protection against the known endothelial injury stimulus Oxidize Low Density Lipoprotein (OxLDL). The goal of current study is to determine the effects of endothelial-specific HDAC2 overexpression on endothelial dysfunction and atherogenesis in vivo . Approach and Results: To study the effect of endothelial HDAC2 overexpression on vascular function and atherogenesis, we generated and characterized an endothelial specific human HDAC2 overexpressing transgenic mouse (HDAC2-Tg) under the control of the tie2 promoter. The founder HDAC2-overexpressing mice appear to have a normal phenotype- normal weight, mean arterial blood pressure (MAP) and pulse wave velocity (PWV). Isolated intact aortas from endothelial-specific overexpressing HDAC2 transgenic mice (HDAC2-Tg) exhibited a healthier vascular function profile with higher nitric oxide levels and less OxLDL-mediated vascular dysfunction. Further, we induced atherogenesis in C57BL6 and HDAC2-Tg mice by injecting adeno-associated viruses (AAV) encoding PCSK9 (D377Y) under the control of a liver-specific promoter by tail vein injection followed by high fat diet regimen for 12 weeks and measured endothelium-dependent vasorelaxation in isolated blood vessels, pulse wave velocity, an index of vascular stiffness and mean arterial blood pressure. HDAC2-Tg exhibited protected endothelial dependent vascular relaxation and no significant changes in MAP and PWV as compared to control mice. Conclusion: HDAC2 is a critical regulator of endothelial function. Overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis.

Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor.

The role of prostaglandin A2 (PGA2) in modulation of vascular endothelial function is unknown. We investigated effects of PGA2 on pulmonary endothelial cell (EC) permeability and inflammatory activation and identified a receptor mediating these effects. PGA2 enhanced the EC barrier and protected against barrier dysfunction caused by vasoactive peptide thrombin and proinflammatory bacterial wall lipopolysaccharide (LPS). Receptor screening using pharmacological and molecular inhibitory approaches identified EP4 as a novel PGA2 receptor. EP4 mediated barrier-protective effects of PGA2 by activating Rap1/Rac1 GTPase and protein kinase A targets at cell adhesions and cytoskeleton: VE-cadherin, p120-catenin, ZO-1, cortactin, and VASP. PGA2 also suppressed LPS-induced inflammatory signaling by inhibiting the NFκB pathway and expression of EC adhesion molecules ICAM1 and VCAM1. These effects were abolished by pharmacological or molecular inhibition of EP4. In vivo, PGA2 was protective in two distinct models of acute lung injury (ALI): LPS-induced inflammatory injury and two-hit ALI caused by suboptimal mechanical ventilation and injection of thrombin receptor-activating peptide. These protective effects were abolished in mice with endothelial-specific EP4 knockout. The results suggest a novel role for the PGA2-EP4 axis in vascular EC protection that is critical for improvement of pathological states associated with increased vascular leakage and inflammation.

Study on the physicochemical properties and anti-inflammatory effects of paeonol in rats with TNBS-induced ulcerative colitis

Paeonol, an active component from Paeonia suffruticosa Andr., has a variety of biological activities, such as vascular endothelial cell protection, anti-oxidation, and anti-inflammation. The aim of this study was to investigate the basic physicochemical properties of paeonol, including solubility, oil–water partition coefficient, and permeability. Then evaluated the anti-inflammatory effects of paeonol were evaluated on 2,4,6-trinitrobenzenesulfonic acid-induced ulcerative colitis in rats. The rats were divided randomly into 6 groups, namely, normal, model, paeonol-treated (100, 200, and 400mg/kg), and positive. Each group had 10 rats. Inhibition effects were evaluated by the disease activity index (DAI), colon weight/length ratio, as well as macroscopical and histological evaluations. Serum interleukin (IL)-17, IL-6 and transforming growth factor beta 1 (TGF-β1) levels were determined by enzyme-linked immunosorbent assay. The solubility and oil–water partition coefficient of paeonol in different phosphate buffer solutions were 284.06–598.23 and 461.97–981.17μg/mL, respectively. The effective passive permeability value Pe was 23.49×10−6cm/s. In terms of anti-inflammatory results, compared with the model group, treatment with 200 and 400mg/kg doses of paeonol had significantly decreased DAI, colon weight/length ratio, and macroscopic and histopathological scores. Furthermore, the serum levels of IL-17 and IL-6 were significantly reduced, whereas the TGF-β1 level was increased in the two paeonol-treated groups (medium- and high-dose group). Therefore, paeonol had poor water solubility, but oral absorption was good. In addition, paeonol had therapeutic effects on ulcerative colitis, and the therapeutic efficacy was dose dependent. The results presented in this study provide evidence for the development of a novel therapeutic agent in the treatment of UC. However, whether this agent could have therapeutic benefit or adverse effects in human IBD remains to be fully explored.

Peripheral brain-derived neurotrophic factor is related to cardiovascular risk factors in active and inactive elderly men.

Regular exercise plays an important preventive and therapeutic role in heart and vascular diseases, and beneficially affects brain function. In blood, the effects of exercise appear to be very complex and could include protection of vascular endothelial cells via neurotrophic factors and decreased oxidative stress. The purpose of this study was to identify the age-related changes in peripheral brain-derived neurotrophic factor (BDNF) and its relationship to oxidative damage and conventional cardiovascular disease (CVD) biomarkers, such as atherogenic index, C-reactive protein (hsCRP) and oxidized LDL (oxLDL), in active and inactive men. Seventeen elderly males (61-80 years) and 17 young males (20-24 years) participated in this study. According to the 6-min Åstrand-Rhyming bike test, the subjects were classified into active and inactive groups. The young and elderly active men had a significantly better lipoprotein profile and antioxidant status, as well as reduced oxidative damage and inflammatory state. The active young and elderly men had significantly higher plasma BDNF levels compared to their inactive peers. BDNF was correlated with VO2max (r=0.765, P<0.001). In addition, we observed a significant inverse correlation of BDNF with atherogenic index (TC/HDL), hsCRP and oxLDL. The findings demonstrate that a high level of cardiorespiratory fitness reflected in VO2max was associated with a higher level of circulating BDNF, which in turn was related to common CVD risk factors and oxidative damage markers in young and elderly men.

Protection of vascular endothelial cells from high glucose-induced cytotoxicity by emodin

Induction of endothelial cytotoxicity by hyperglycemia in diabetes has been widely accepted. Emodin is a natural anthraquinone in rhubarb used for treatment of diabetes, but its mechanism of action is not fully understood. This study aimed to examine the potential beneficial effects of emodin on endothelial cytotoxicity caused by high glucose milieu. Culture of human umbilical vein endothelial cells (HUVECs) with high concentrations of glucose resulted in damage to the cells, leading to decreased formazan products by 14–27%, reduced DNA contents by 12–19%, and increased hypodiploid apoptosis by 40–109%. These adverse effects of high glucose could be prevented to a large extent by co-culture with 3μM of emodin which per se did not affect HUVECs viability. In addition, CCL5 expression of HUVECs cultured in high glucose medium was significantly elevated at both mRNA and protein levels, an effect abolished after treatment with emodin. Moreover, the enhanced adhesion of monocytes to HUVECs (2.1–2.2 fold over control) and elevated chemotaxis activities (2.3–2.4 fold over control) in HUVECs cultured in high glucose medium were completely reversed by emodin. Emodin also suppressed activation of p38 MAPK and ERK1/2 due to high glucose. Our data demonstrated that endothelial cytotoxicity occurred clearly when HUVECs were exposed to high glucose milieu and emodin was able to alleviate the impairments. The protective effects of emodin might be related to the inhibition of CCL5 expression and subsequent cell stress/inflammatory events possibly mediated by activation of MAPK signaling pathways.