scholarly journals Pathophysiological Association between Diabetes Mellitus and Endothelial Dysfunction

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1306
Author(s):  
Tatsuya Maruhashi ◽  
Yukihito Higashi
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Critical Role ◽  
No Production ◽  
Chronic Hyperglycemia ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Patients With Diabetes ◽  
Glucose Fluctuations

Endothelial dysfunction plays a critical role in atherosclerosis progression, leading to cardiovascular complications. There are significant associations between diabetes mellitus, oxidative stress, and endothelial dysfunction. Oxidative stress is increased by chronic hyperglycemia and acute glucose fluctuations induced by postprandial hyperglycemia in patients with diabetes mellitus. In addition, selective insulin resistance in the phosphoinositide 3-kinase/Akt/endothelial nitric oxide (NO) synthase pathway in endothelial cells is involved in decreased NO production and increased endothelin-1 production from the endothelium, resulting in endothelial dysfunction. In a clinical setting, selecting an appropriate therapeutic intervention that improves or augments endothelial function is important for preventing diabetic vascular complications. Hypoglycemic drugs that reduce glucose fluctuations by decreasing the postprandial rise in blood glucose levels, such as glinides, α-glucosidase inhibitors and dipeptidyl peptidase 4 inhibitors, and hypoglycemic drugs that ameliorate insulin sensitivity, such as thiazolidinediones and metformin, are expected to improve or augment endothelial function in patients with diabetes. Glucagon-like peptide 1 receptor agonists, metformin, and sodium-glucose cotransporter 2 inhibitors may improve endothelial function through multiple mechanisms, some of which are independent of glucose control or insulin signaling. Oral administration of antioxidants is not recommended in patients with diabetes due to the lack of evidence for the efficacy against diabetic complications.

Abstract 231: Cloning, Expression, Charecterization and Redox Regulation of Human DDAH-1: Implications in NO Regulation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Scott P Forbes ◽  
Lawrence Druhan ◽  
Arthur Pope ◽  
Arturo Cardounel
Keyword(s):  
Oxidative Stress ◽  
Enzyme Activity ◽  
Endothelial Dysfunction ◽  
Critical Role ◽  
Oxidation Products ◽  
Kinetic Properties ◽  
No Production ◽  
Lipid Peroxidation Product ◽  
Lipid Oxidation Products ◽  
Nos Inhibitors

Altered NO biosynthesis is known to play a central role in the pathogenesis of endothelial dysfunction. It is hypothesized that reduced NO bioavailability may result from an increase in endogenous NOS inhibitors, ADMA and NMMA, which are normally metabolized by dimethyarginine dimethylamine hydrolase (DDAH). DDAH hydrolyzes side-chain methylated L-arg and thus regulates the activity of NOS. To date, the few studies published on DDAH have been carried out using enzyme purified from pseudomonas or rat kidney homogenates. Herein we report the cloning, expression and kinetic properties of hDDAH-1 and its regulation by redox environment. Human DDAH-1 was cloned into an e. coli expression vector and recombinant hDDAH-1 purifed to > 95% purity. Kinetic studies from the enzyme demonstrated Km values of 18.2 and 27.1 μM and Vmax values of 303 and 182 nmols/mg/min for ADMA and L-NMMA, respectively. Oxidant exposure studies were performed to determine the effects of reactive oxygen and reactive nitrogen species on DDAH activity. Results demonstrated that low level oxidant exposure had little effect on enzyme activity and that concentrations approaching 1 mM were needed to confer significant enzyme inhibition. However, exposure of hDDAH-1 to lipid oxidation products, such as 4-HNE, dose dependently inhibited DDAH activity with 15% inhibition observed at 10 μM, 50% inhibition at 50 μM and near complete inhibition at 100 μM. These levels represent pathophysiological concentrations of this lipid peroxidation product and suggest that DDAH activity can be impaired under conditions of increased oxidative stress. Proteomic analysis revealed that exposure of hDDAH-1 to 4-HNE results in Schiff base adduct formation of critical amino acid residues located within the enzyme active site. Thus, 4-HNE directly modifies hDDAH-1 with subsequent loss of enzyme activity. To determine whether this loss of DDAH activity results in NOS impairment, studies were performed using cultured endothelial cells. Results demonstrated that exposure of cells to 4-HNE (50 μM) inhibited eNOS derived NO production by 45% and reduced cellular DDAH activity by 41%. These results demonstrate a critical role for DDAH in the pathogenesis of endothelial dysfunction under conditions of oxidative stress.

scholarly journals Vena cava presents endothelial dysfunction prior to thoracic aorta in heart failure: the pivotal role of nNOS uncoupling/ oxidative stress

2021 ◽  
Author(s):  
Patrizia Dardi ◽  
Laís Rossi Perazza ◽  
Gisele Kruger Couto ◽  
Gianne Paul Campos ◽  
Luciano dos Santos Aggum Capettini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Thoracic Aorta ◽  
Vascular Reactivity ◽  
Vena Cava ◽  
Coronary Artery Occlusion ◽  
H2o2 Production ◽  
No Production

Arterial endothelial dysfunction has been extensively studied in heart failure (HF). However little is known about the adjustments shown by the venous system in this condition. Considering that inferior vena cava (VC) tone could influence cardiac performance and HF prognosis, the aim of the present study was to assess the VC and thoracic aorta (TA) endothelial function of HF-post-myocardial infarction (MI) rats, comparing both endothelial responses and signaling pathways developed. Vascular reactivity of TA and VC from HF post-MI and sham operated (SO) rats was assessed with a wire myograph, four weeks after coronary artery occlusion surgery. Nitric oxide (NO), H2O2 production and oxidative stress were evaluated in situ with fluorescent probes, whilst protein expression and dimer/monomer ratio was assessed by western blot. VC from HF rats presented endothelial dysfunction, while TA exhibited higher acetylcholine (ACh)-induced vasodilation when compared to vessels from SO rats. TA exhibited increased ACh-induced NO production due to a higher coupling of endothelial and neuronal NO synthases isoforms (eNOS, nNOS), and enhanced expression of antioxidant enzymes. These adjustments, however, were absent in VC of HF post-MI rats, which exhibited uncoupled nNOS, oxidative stress and higher H2O2 bioavailability. Altogether, this study suggests a differential regulation of endothelial function between VC and TA of HF post-MI rats, most likely due to nNOS uncoupling and compromised antioxidant defense.

scholarly journals Overexpression of E3 ubiquitin ligase Cbl attenuates endothelial dysfunction in diabetes mellitus by inhibiting the JAK2/STAT4 signaling and Runx3-mediated H3K4me3

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qingsong Jin ◽  
Liangyan Lin ◽  
Tiantian Zhao ◽  
Xiaoyan Yao ◽  
Yaqin Teng ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Ubiquitin Ligase ◽  
Umbilical Vein ◽  
E3 Ubiquitin Ligase ◽  
Rat Tissues ◽  
No Production ◽  
Common Chronic Disease

Abstract Background Diabetes mellitus (DM), a most common chronic disease, is featured with impaired endothelial function and bioavailability of nitric oxide (NO), while E3 ubiquitin ligase appears to alleviate endothelial dysfunction as a promising option for DM treatment. Herein, we aimed to determine whether E3 ubiquitin ligase casitas B-lineage lymphoma (Cbl) alleviates endothelial dysfunction in DM rats by JAK2/STAT4 pathway. Methods A rat model of DM was developed through intraperitoneal injection of streptozotocin, followed by collection of aortic tissues to determine the expression of Cbl, JAK2, runt-related transcription factor 3 (Runx3) and STAT4. Human umbilical vein endothelial cells (HUVECs) were cultured in high glucose (HG) condition to induce DM as an in vitro model. With gain- and loss-function method, we assessed the aberrantly expressed Cb1 on endothelial dysfunction, NO production and apoptosis of HUVECs. Results Cbl was reduced in DM rat tissues and HG-induced HUVECs, where JAK2, Runx3 and STAT4 were elevated. It was found that overexpression of Cbl alleviated endothelial dysfunction by increasing NO production and restoring vasodilation and suppressing apoptosis of HUVECs. Mechanistically, Cb1 enhanced JAK2 ubiquitination and decreased JAK2 and STAT4 expression, where STAT4 improved Runx3 expression by regulating histone H3 lysine 4 trimethylation level. Overexpression of JAK2 and STAT4, or Runx3 increased apoptosis of HUVECs, abrogating the effect of Cb1 on endothelial function. Conclusion In conclusion, Cbl alleviates endothelial dysfunction by inactivation of the JAK2/STAT4 pathway and inhibition of Runx3 expression in DM. These evidence might underlie novel Cbl-based treatment against DM in the future.

scholarly journals Measurement and Clinical Significance of Lipid Peroxidation as a Biomarker of Oxidative Stress: Oxidative Stress in Diabetes, Atherosclerosis, and Chronic Inflammation

Antioxidants ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 72 ◽  
Author(s):  
Fumiaki Ito ◽  
Yoko Sono ◽  
Tomoyuki Ito
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Risk Factors ◽  
Lipid Peroxidation ◽  
Endothelial Dysfunction ◽  
Chronic Inflammation ◽  
Current Knowledge ◽  
Glycation End Products ◽  
Patients With Diabetes ◽  
Stress Oxidative

Endothelial dysfunction is one of the initial steps in the pathogenesis of atherosclerosis and development of cardiovascular disease in patients with diabetes mellitus. Several risk factors are associated with endothelial dysfunction and atherosclerosis, such as hypertension, dyslipidaemia, inflammation, oxidative stress, and advanced glycation-end products. Among these risk factors, oxidative stress is the largest contributor to the formation of atherosclerotic plaques. Measurement of reactive oxygen species (ROS) is still difficult, and assays for the measurement of ROS have failed to show a consistent correlation between pathological states and oxidative stress. To solve this problem, this review summarizes the current knowledge on biomarkers of oxidative stress, especially lipid peroxidation, and discusses the roles of oxidative stress, as measured by indices of lipid peroxidation, in diabetes mellitus, atherosclerosis, and chronic inflammation.

Clinical aspects of reactive oxygen and nitrogen species

2004 ◽  
Vol 71 ◽  
pp. 121-133 ◽  
Author(s):  
Ascan Warnholtz ◽  
Maria Wendt ◽  
Michael August ◽  
Thomas Münzel
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Risk Factor ◽  
Endothelial Dysfunction ◽  
Vascular Tissue ◽  
Rapid Development ◽  
Reactive Oxygen ◽  
Clinical Aspects ◽  
No Production ◽  
Oxygen Species

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.

Evaluation of Salivary Antioxidants and Oxidative Stress Markers in Type 2 Diabetes Mellitus: A Retrospective Cohort Study

2020 ◽  
Vol 20 (4) ◽  
pp. 584-590 ◽  
Author(s):  
Shima Fathi ◽  
Shiva Borzouei ◽  
Mohammad Taghi Goodarzi ◽  
Jalal Poorolajal ◽  
Fatemeh Ahmadi-Motamayel
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Control Group ◽  
Oxidative Stress Markers ◽  
Stress Markers ◽  
Type 2 Dm ◽  
Patients With Diabetes ◽  
The Difference ◽  
And Oxidative Stress

Background: Diabetes Mellitus (DM) is a progressive metabolic disorder. Objective: The aim of this study was to investigate the relationship between antioxidant and oxidative stress markers in the saliva of patients with type 2 DM and a healthy control group. Methods: In this study, 20 patients with diabetes and 20 healthy individuals were evaluated. Salivary antioxidants markers consisted of total antioxidant capacity (TAC), uric acid (UA), peroxidase and catalase. Oxidative stress markers included total oxidant status (TOS), malondealdehyde (MDA) and total thiol (SH). Sialochemical analysis was performed with spectrophotometric assay. All the statistical analyses were conducted using STATA software. Results: TAC decreased significantly in patients with diabetes. Although salivary UA and peroxidase were lower in patients with diabetes compared to the control group, the difference was not significant. Salivary catalase in patients with diabetes was significantly lower than that in the control group. MDA and TOS exhibited significantly higher levels in type 2 DM. SH levels were slightly higher in DM. Conclusions: According to the results of the present study, there were some changes in the salivary levels of some antioxidants and oxidative stress markers in patients with type 2 DM and could be measured as an indicator of serum changes..

scholarly journals GTP Cyclohydrolase I Gene Polymorphisms Are Associated with Endothelial Dysfunction and Oxidative Stress in Patients with Type 2 Diabetes Mellitus

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e108587 ◽  
Author(s):  
Pawel P. Wolkow ◽  
Wladyslaw Kosiniak-Kamysz ◽  
Grzegorz Osmenda ◽  
Grzegorz Wilk ◽  
Beata Bujak-Gizycka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Endothelial Dysfunction ◽  
Gene Polymorphisms ◽  
Gtp Cyclohydrolase I ◽  
And Oxidative Stress ◽  
I Gene

scholarly journals Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Basma Basha ◽  
Samson Mathews Samuel ◽  
Chris R. Triggle ◽  
Hong Ding
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Clinical Trials ◽  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Therapeutic Agents ◽  
Recent Past

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

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