R-(+)-α-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1

2007 ◽  
Vol 293 (3) ◽  
pp. E681-E689 ◽  
Author(s):  
Michaela Artwohl ◽  
Kathrin Muth ◽  
Karin Kosulin ◽  
Rainer de Martin ◽  
Thomas Hölzenbein ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Protein Expression ◽  
Lipoic Acid ◽  
Kinase Inhibitors ◽  
Vascular Complications ◽  
Retinoblastoma Protein ◽  
Cell Cycle Distribution ◽  
Diabetic Patients ◽  
Tnf Α

Lipoic acid was recently demonstrated to improve endothelial dysfunction or retinopathy not only in rats but also in diabetic patients. We tested the hypothesis that R-(+)-α-lipoic acid (LA) directly affects human endothelial cell (EC) function (e.g., apoptosis, proliferation, and protein expression), independent of the cells' vascular origin. Macrovascular EC (macEC), isolated from umbilical (HUVEC) and adult saphenous veins and from aortae, as well as microvascular EC (micEC) from retinae, skin, and uterus, were exposed to LA (1 μmol/l–1 mmol/l) with/without different stimuli (high glucose, TNF-α, VEGF, wortmannin, LY-294002). Apoptosis, proliferation, cell cycle distribution, and protein expression were determined by DNA fragmentation assays, [3H]thymidine incorporation, FACS, and Western blot analyses, respectively. In macro- and microvascular EC, LA (1 mmol/l) reduced ( P < 0.05) basal (macEC, −36 ± 4%; micEC, −46 ± 6%) and stimulus-induced (TNF-α: macEC, −75 ± 11%; micEC, −68 ± 13%) apoptosis. In HUVEC, inhibition of apoptosis by LA (500 μmol/l) was paralleled by reduction of NF-κB. LA's antiapoptotic activity was reduced by PI 3-kinase inhibitors (wortmannin, LY-294002), being in line with LA-induced Akt phosphorylation (Ser437, +159 ± 43%; Thr308, +98 ± 25%; P < 0.01). LA (500 μmol/l) inhibited ( P < 0.001) proliferation of macEC (−29 ± 3%) and micEC (−29 ± 3%) by arresting the cells at the G1/S transition due to an increased ratio of cyclin E/p27Kip (4.2-fold), upregulation of p21WAF-1/Cip1 (+104 ± 21%), and reduction of cyclin A (−32 ± 11%), of hyperphosphorylated retinoblastoma protein (macEC: −51 ± 7%; micEC: −50 ± 15%), and of E2F-1 (macEC: −48 ± 3%; micEC: −31 ± 10%). LA's ability to inhibit apoptosis and proliferation of ECs could beneficially affect endothelial dysfunction, which precedes manifestation of late diabetic vascular complications.

Relationship of Soluble RAGE and RAGE Ligands HMGB1 and EN-RAGE to Endothelial Dysfunction in Type 1 and Type 2 Diabetes Mellitus

2012 ◽  
Vol 120 (05) ◽  
pp. 277-281 ◽  
Author(s):  
J. Škrha Jr ◽  
M. Kalousová ◽  
J. Švarcová ◽  
A. Muravská ◽  
J. Kvasnička ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Dysfunction ◽  
Advanced Glycation Endproducts ◽  
Vascular Complications ◽  
Diabetic Patients ◽  
Glycation Endproducts ◽  
Diabetic Vascular Complications ◽  
Soluble Rage

AbstractReceptor for advanced glycation endproducts (RAGE) plays the essential role in the pathogenesis of diabetic vascular complications. The aim of the study was to compare concentration of soluble RAGE and its ligands (EN-RAGE and HMGB1) with different biochemical parameters in Type 1 (T1DM) and Type 2 (T2DM) diabetes mellitus.Total number of 154 persons (45 T1DM, 68 T2DM, 41 controls) was examined and concentrations of sRAGE, EN-RAGE and HMGB1 were measured and compared to diabetes control, albuminuria, cell adhesion molecules and metalloproteinases (MMPs).Mean serum sRAGE concentration was higher in T1DM as compared to controls (1137±532 ng/l vs. 824±309 ng/l, p<0.01). Similarly, EN-RAGE was significantly higher in both diabetic groups (p<0.001) and HMGB1 concentrations were elevated in T2DM patients (p<0.01). Significant relationship was found between MMP9 and HMGB1 and EN-RAGE in diabetic patients. Inverse relationship was observed between MMP2 and MMP9 in both types of diabetic patients (r= − 0.602, p<0.002 and r= − 0.771, p<0.001). Significant positive correlation was found between sRAGE and ICAM-1, VCAM-1 or vWF (p<0.01 to p<0.001).We conclude that serum sRAGE and RAGE ligands concentrations reflect endothelial dysfunction developing in diabetes.

scholarly journals Targeting QKI-7 in vivo restores endothelial cell function in diabetes

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chunbo Yang ◽  
Magdalini Eleftheriadou ◽  
Sophia Kelaini ◽  
Thomas Morrison ◽  
Marta Vilà González ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
Vascular Endothelial Cell ◽  
Vascular Complications ◽  
Limb Ischemia ◽  
Limb Amputation ◽  
Diabetic Patients ◽  
Ips Cell ◽  
Endothelial Cell Function

Abstract Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. This study discovers significant upregulation of Quaking-7 (QKI-7) in iPS cell-derived ECs when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 is also highly expressed in human coronary arterial ECs from diabetic donors, and on blood vessels from diabetic critical limb ischemia patients undergoing a lower-limb amputation. QKI-7 expression is tightly controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation is correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion. RNA immunoprecipitation (RIP) and mRNA-decay assays reveal that QKI-7 binds and promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene/protein 6 (TSG-6). When hindlimb ischemia is induced in diabetic mice and QKI-7 is knocked-down in vivo in ECs, reperfusion and blood flow recovery are markedly promoted. Manipulation of QKI-7 represents a promising strategy for the treatment of diabetic vascular complications.

scholarly journals Epigenetic regulation in diabetic vascular complications

2019 ◽  
Vol 63 (4) ◽  
pp. R103-R115 ◽  
Author(s):  
Jiayu Jin ◽  
Xinhong Wang ◽  
Xiuling Zhi ◽  
Dan Meng
Keyword(s):  
Endothelial Dysfunction ◽  
Epigenetic Regulation ◽  
Epigenetic Modification ◽  
Vascular Complications ◽  
Integrated System ◽  
Metabolic Memory ◽  
Diabetic Patients ◽  
Epigenetic Alterations ◽  
Diabetic Vascular Complications ◽  
Legacy Effect

Cardiovascular disease (CVD), the main complication of diabetes mellitus (DM), accounts for a high percentage of mortality in diabetic patients. Endothelial dysfunction is a major causative event in the pathogenesis of diabetes-related vascular disease and the earliest symptom of vascular injury. Epigenetic modification plays a key role in the initiation, maintenance, and progression of both endothelial dysfunction and diabetes. Epigenetic alterations respond to the environment and mediate the ‘legacy effect’ of uncontrolled hyperglycaemia early in the disease despite thorough glycaemic control in a phenomenon called metabolic memory. Therefore, an understanding of the integrated system of different epigenetic mechanisms in DM and its vascular complications is urgently needed. This review summarizes aberrant epigenetic regulation under diabetic conditions, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs). Understanding the connections between these processes and DM may reveal a novel potential therapeutic target for diabetic vascular complications.

scholarly journals The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection

2020 ◽  
Vol 21 (23) ◽  
pp. 9309
Author(s):  
Jessica Maiuolo ◽  
Rocco Mollace ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
Cristina Carresi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Blood Vessels ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Vascular Complications ◽  
Therapeutic Interventions ◽  
The Impact

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells, which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of a SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to a detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with the ACE2 receptor located in the endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function, which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease, leading to irreversible tissue damage and death of people with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated with the interaction of SARS CoV-2 with the ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.

scholarly journals Suppressing or blocking Fis1 reverses diabetic endothelial dysfunction in human resistance arteries

2020 ◽  
Author(s):  
Mamatha Kakarla ◽  
John M. Egner ◽  
Jingli Wang ◽  
Megan C. Harwig ◽  
Kelsey A. Meacham ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
High Glucose ◽  
Vascular Complications ◽  
The United States ◽  
Diabetic Patients ◽  
Dependent Manner ◽  
Resistance Arteries ◽  
Low Glucose

AbstractMitochondrial dysfunction drives the development of vascular endothelial dysfunction in type 2 diabetes (T2DM) with increased fragmentation of mitochondrial networks from increased Fis1 expression; whether suppressing or blocking Fis1 expression or activity can reverse endothelial dysfunction remains unknown. To address this question, resistance arterioles from healthy humans and those with T2DM were transfected with Fis1 siRNA and exposed to normal glucose, low glucose or high glucose conditions. Fis1 knockdown improved endothelium dependent vasodilation in T2DM arterioles, and blocked high- and low-glucose impairment in healthy vessels. Fis1 knockdown preserved NO bioavailability and improved endothelial layer integrity of cells exposed to high or low glucose. Fis1 knockdown had no significant effect on the expression of other mitochondrial dynamics or autophagy proteins, and had no effect on endothelial cell metabolism suggesting its suitability for pharmacological inhibition. For this, we designed pep213 to inhibit Fis1 activity (Kd ~3-7 μM) and demonstrate its specificity by NMR. Application of a cell permeant pep213 improved endothelium-dependent vasodilation in T2DM and non-T2DM vessels exposed to high glucose in an NO-dependent manner suggesting that targeting Fis1 may reduce vascular complications in T2DM.One Sentence SummaryMicro- and macro-vascular complications in type 2 diabetes mellitus (T2DM) continue to be major health burdens in the United States and we identify a new therapeutic route to treatment by showing that either a novel peptide inhibitor, or genetic silencing, of mitochondrial fission protein 1 reverses poor vasodilation of human resistance arteries from diabetic patients.

scholarly journals The effect of α-lipoic acid treatment on plasma asymmetric dimethylarginine, a biomarker of endothelial dysfunction in diabetic neuropathy

2020 ◽  
Author(s):  
Ferenc Sztanek ◽  
Hajnalka Lőrincz ◽  
Ágnes Molnár ◽  
Anita Szentpéteri ◽  
Eszter Zöld ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Diabetic Neuropathy ◽  
Asymmetric Dimethylarginine ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Tnf Α ◽  
Type 2 Diabetic

IntroductionDiabetic neuropathy may develop on a background of hyperglycaemia and is associated with increased oxidative stress. Elevated asymmetric dimethylarginine (ADMA) levels are linked to oxidative stress reducing the synthesis of nitric oxide (NO) by uncoupling NO synthase. Oxidative stress induces considerable changes in nerve conduction velocity in diabetic patients. There is strong evidence that α-lipoic acid (ALA) as an antioxidant may improve nerve conduction and relieve neuropathic symptoms. We aimed to investigate the relationship between endothelial dysfunction and NO synthesis in type 2 diabetic patients with peripheral neuropathy after ALA treatment.Material and methodsFifty-four type 2 diabetic patients with neuropathy were included in the study. Serum ADMA concentration, ICAM-1, VCAM-1, oxidised low-density lipoprotein (oxLDL), and TNF-α levels were determined with Enzyme-Linked Immunosorbent Assay (ELISA). Nitric oxide concentration was measured by Griess reaction. Peripheral sensory nerve function was assessed by current perception threshold (CPT) testing. Autonomic function was assessed by Ewing’s five standard cardiovascular reflex tests composite autonomic score (CAS).ResultsAsymmetric dimethylarginine levels were significantly decreased (0.62 ±0.11 vs. 0.53 ±0.11 µmol/l, p < 0.001), as well as TNF-α concentrations (1.21 ±0.42 pg/ml vs. 1.05 ±0.5 pg/ml, p < 0.05), while NO levels were significantly increased (16.78 ±11.1 vs. 21.58 ±8.84 µmol/l, p < 0.05) after six-months of 600 mg/day ALA treatment. VCAM-1, ICAM-1, and oxLDL levels did not change significantly. The CPT and CAS significantly improved after ALA treatment. The improvement of CPT values was correlated positively with the change of ADMA levels (r = 0.58, p < 0.001). The change in ADMA level was more pronounced in responder patients based on both CPT and CAS.ConclusionsOur results suggest that ALA supplementation improves endothelial function characterised by serum levels of ADMA and TNF-α in patients with diabetic neuropathy. Changes in serum ADMA levels may predict the clinical response to ALA treatment.

scholarly journals The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection

2020 ◽  
Author(s):  
Jessica Maiuolo ◽  
Rocco Mollace ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
Cristina Carresi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Blood Vessels ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Vascular Complications ◽  
Therapeutic Interventions ◽  
The Impact

Abstract: SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with ACE2 receptor located in endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease leading to irreversible tissue damage and death of patients with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated to the interaction of SARS CoV-2 with ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.

scholarly journals Platelet-derived calpain cleaves the endothelial protease-activated receptor 1 to induce vascular inflammation in diabetes

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Anastasia Kyselova ◽  
Amro Elgheznawy ◽  
Ilka Wittig ◽  
Juliana Heidler ◽  
Alexander W. Mann ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Inflammation ◽  
Vascular Complications ◽  
Cysteine Proteases ◽  
Calpain Inhibitor ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Endothelial Protein C Receptor ◽  
Tnf Α ◽  
Protease Activated Receptor 1

AbstractDiabetes mellitus is a major risk factor for cardiovascular disease. Platelets from diabetic patients are hyperreactive and release microparticles that carry activated cysteine proteases or calpains. Whether platelet-derived calpains contribute to the development of vascular complications in diabetes is unknown. Here we report that platelet-derived calpain1 (CAPN1) cleaves the protease-activated receptor 1 (PAR-1) on the surface of endothelial cells, which then initiates a signaling cascade that includes the activation of the tumor necrosis factor (TNF)-α converting enzyme (TACE). The latter elicits the shedding of the endothelial protein C receptor and the generation of TNF-α, which in turn, induces intracellular adhesion molecule (ICAM)-1 expression to promote monocyte adhesion. All of the effects of CAPN1 were mimicked by platelet-derived microparticles from diabetic patients or from wild-type mice but not from CAPN1−/− mice, and were not observed in PAR-1-deficient endothelial cells. Importantly, aortae from diabetic mice expressed less PAR-1 but more ICAM-1 than non-diabetic mice, effects that were prevented by treating diabetic mice with a calpain inhibitor as well as by the platelet specific deletion of CAPN1. Thus, platelet-derived CAPN1 contributes to the initiation of the sterile vascular inflammation associated with diabetes via the cleavage of PAR-1 and the release of TNF-α from the endothelial cell surface.

scholarly journals Cinnamaldehyde Prevents Endothelial Dysfunction Induced by High Glucose by Activating Nrf2

2015 ◽  
Vol 36 (1) ◽  
pp. 315-324 ◽  
Author(s):  
Fang Wang ◽  
Chunhua Pu ◽  
Peng Zhou ◽  
Peijian Wang ◽  
Dengpan Liang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
High Glucose ◽  
Vascular Complications ◽  
Causative Factor ◽  
Ros Generation ◽  
Diabetic Patients ◽  
Related Factor ◽  
Flavor Compound ◽  
Downstream Target ◽  
Cinnamon Essential Oil

Background/Aims: It is well documented that hyperglycemia-induced oxidative stress is an important causative factor of endothelial dysfunction. Cinnamaldehyde (CA) is a key flavor compound in cinnamon essential oil that can enhance the antioxidant defense against reactive oxygen species (ROS) by activating NF-E2-related factor 2 (Nrf2), which has been shown to have a cardiovascular protective effect, but its role in endothelial dysfunction induced by high glucose is unknown. Methods: Dissected male C57BL/6J mouse aortic rings and HUVECs were cultured in normal glucose(NG 5.5 mM) or high glucose(HG 30.0 mM) DMEM treatment with or without CA (10 µM). Results: Treatment with CA protected the endothelium relaxation, inhibited ROS generation and preserved nitric oxide (NO) levels in the endothelium of mouse aortas treated with high glucose . CA up-regulated Nrf2 expression, promoted its translocation to the nucleus‚and increased HO-1, NQO1, Catalase and Gpx1 expression under high glucose condition. The increased level of nitrotyrosine in HUVECs under high glucose was also attenuated by treatment with CA. Dihydroethidium (DHE) and DAF-2DA staining indicated that CA inhibited the ROS generation and preserved the NO levels in HUVECs, but these effects were reversed by Nrf2-siRNA in high glucose conditions. Conclusion: Our results indicated that CA protected endothelial dysfunction under high glucose conditions and this effect was mediated by Nrf2 activation and the up-regulation of downstream target proteins. CA administration may represent a promising intervention in diabetic patients who are at risk for vascular complications.

scholarly journals Osteoprotegerin as a Marker of Atherosclerosis in Diabetic Patients

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Areti Augoulea ◽  
Nikolaos Vrachnis ◽  
Irene Lambrinoudaki ◽  
Konstantinos Dafopoulos ◽  
Zoe Iliodromiti ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Mineral Metabolism ◽  
Vascular Complications ◽  
Diabetic Patients ◽  
Noninvasive Methods ◽  
Receptor Activator ◽  
Patients With Diabetes ◽  
Few Data ◽  
The Relationship

Atherosclerosis is the principal cause of cardiovascular disease (CVD) and has many risk factors, among which is diabetes. Osteoprotegerin (OPG) is a soluble glycoprotein, involved in bone metabolism. OPG is also found in other tissues, and studies have shown that it is expressed in vascular smooth muscle cells. OPG has been implicated in various inflammations and also has been linked to diabetes mellitus. Increased serum OPG levels were found in patients with diabetes and poor glycemic control. Furthermore, prepubertal children with type 1 diabetes have significantly increased OPG levels. Receptor activator of nuclear factor kappa-B ligand (RANKL) is not found in the vasculature in normal conditions, but may appear in calcifying areas. OPG and RANKL are important regulators of mineral metabolism in both bone and vascular tissues. Few data are available on the relationship between plasma OPG/RANKL levels and endothelial dysfunction as assessed using noninvasive methods like ultrasound indexes, neither in the general population nor, more specifically, in diabetic patients. The aim of our review study was to investigate, based on the existing data, these interrelationships in order to identify a means of predicting, via noninvasive methods, later development of endothelial dysfunction and vascular complications in diabetic patients.

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