Relationship of glycation, antioxidant status and oxidativestress to vascular endothelial damage in diabetes

Wen, Yujun; Skidmore, J. C.; Porter-Turner, M. M.; Rea, Carol; Khokher, M. A.; Singh, Baldev

doi:10.1046/j.1463-1326.2002.00212.x

Cited by 47 publications

(22 citation statements)

References 19 publications

(20 reference statements)

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“…Vascular NO is critical for normal vasodilatation and endothelial function, and impairment of NO bioavailability and the NO-cyclic guanosine monophosphate (cGMP)-cGMP-dependent protein kinases (PKG) signaling cascade can lead to endothelial dysfunction [3]. A number of clinical studies have shown that hyperglycemia and increased AGEs are key factors in potentiating vascular inflammation and increasing levels of reactive oxygen species (ROS) and oxidative stress [4], [5]. This vascular milieu of elevated inflammation, impaired NO bioavailability, and oxidative stress plays an integral role in the progression of atherosclerosis and subsequently acute coronary syndromes culminating in significant morbidity and mortality of the diabetic patient [6].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, eNOS knockout mice had decreased oxygen consumption, increased weight gain and were resistant to insulin [11]. In addition, several studies have indicated that insulin resistance itself may impair NO release and damage the endothelium through mechanisms that are reciprocally interconnected [4], [5]. For example, chronic hyperglycemia has been shown to increase circulating levels of inflammatory cytokines, chemokines, and expression of intracellular adhesion molecule-1, hence contributing further to this pathognomonic state [12].…”

Section: Introductionmentioning

confidence: 99%

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Anti-Inflammatory and Cardioprotective Effects of Tadalafil in Diabetic Mice

et al. 2012

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BackgroundInsulin resistance impairs nitric oxide (NO) bioavailability and obesity promotes a state of chronic inflammation and damages the vascular endothelium. Phosphodiesterase-5 inhibitors restore NO signaling and may reduce circulating inflammatory markers, and improve metabolic parameters through a number of mechanisms. We hypothesized that daily administration of the PDE-5 inhibitor, tadalafil (TAD) will attenuate inflammation, improve fasting plasma glucose and triglyceride levels, body weight, and reduce infarct size after ischemia/reperfusion injury in obese, diabetic mice.MethodsTwenty leptin receptor null (db/db) mice underwent treatment with TAD (1 mg/Kg) or 10% DMSO for 28 days. Body weight and fasting plasma glucose levels were determined weekly. Upon completion, hearts were isolated and subjected to 30 min global ischemia followed by 60 min reperfusion in a Langendorff model. Plasma samples were taken for cytokine analysis and fasting triglyceride levels. Infarct size was measured using computer morphometry of tetrazolium stained sections. Additionally, ventricular cardiomyocytes were isolated and subjected to 40 min of simulated ischemia and reoxygenation. Necrosis was determined using trypan blue exclusion and LDH release assay and apoptosis was assessed by TUNEL assay after 1 h or 18 h of reoxygenation, respectively.ResultsTreatment with TAD caused a reduction in infarct size in the diabetic heart (23.2±1.5 vs. 47.8±3.7%, p<0.01, n = 6/group), reduced fasting glucose levels (292±31.8 vs. 511±19.3 mg/dL, p<0.001) and fasting triglycerides (43.3±21 vs. 129.7±29 mg/dL, p<0.05) as compared to DMSO, however body weight was not significantly reduced. Circulating tumor necrosis factor-α and interleukin-1β were reduced after treatment compared to control (257±16.51 vs. 402.3±17.26 and 150.8±12.55 vs. 264±31.85 pg/mL, respectively; P<0.001) Isolated cardiomyocytes from TAD-treated mice showed reduced apoptosis and necrosis.ConclusionWe have provided the first evidence that TAD therapy ameliorates circulating inflammatory cytokines and chemokines in a diabetic animal model while improving fasting glucose levels and reducing infarct size following ischemia-reperfusion injury in the heart.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory and Cardioprotective Effects of Tadalafil in Diabetic Mice

et al. 2012

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“…Diabetic endothelial dysfunction is the result of imbalance between reactive oxygen species (ROS), increased via antioxidant and glycation pathways, and the production and availability of NO, that is reduced (5,6,7,8). In addition, an increase in serum levels of vasoconstrictors, such as endothelin 1 (ET1) (9), and an impairment of several hemodynamic parameters, such as flow-mediated dilation (FMD) at brachial artery, intima-media thickness, and blood pressure (10), were described.…”

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confidence: 99%

THERAPY OF ENDOCRINE DISEASE: Effects of chronic use of phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: a meta-analysis

Santi

Giannetta

Isidori

et al. 2015

European Journal of Endocrinology

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Objective: Diabetes mellitus (DM) is associated with endothelial dysfunction, reducing nitric oxide-dependent vasodilation, and increasing production of pro-inflammatory factors, leading to an increased risk of long-term cardiovascular disease. As the effects of phosphodiesterase 5 inhibitors (PDE5i) on endothelial function have not been systematically investigated, we conducted a meta-analysis of available randomized clinical trials (RCTs). Design: A thorough search of the literature was carried out. Relevant studies were considered according to RCT study design, enrollment of men with type 2 DM, chronic administration of PDE5i, and evaluation of endothelial function through both hemodynamic and endothelial inflammation-related parameters. Results: Fifteen studies fulfilled the eligibility criteria but only six RCTs met the inclusion criteria and were analyzed for 476 diabetic men, 239 randomized to Sildenafil, and 237 to placebo respectively. Four RCTs evaluated flow-mediated dilation (FMD), demonstrating a weighted mean increase of 2.19% (95% CI 0.48 to 3.90). This result showed a high heterogeneity (I 2 : 98%). Thus, a further sub-group meta-analysis was performed and this analysis confirmed a significant, Sildenafil-related FMD improvement. Sildenafil improved endothelin 1 and high sensitivity C-reactive protein by wK0.94 pg/ml and K0.36 mg/l, respectively, not reaching statistical significance (PZ0.69 and PZ0.22 respectively). Finally, Sildenafil administration significantly reduced serum levels of interleukin 6 (IL6, K0.82 pg/ml; 95% CI K1.58 to K0.07). Conclusion: This meta-analysis suggests a beneficial effect of chronic PDE5i administration on endothelial function. Chronic Sildenafil administration seems to improve hemodynamic (FMD) and serum pro-inflammatory makers (IL6) in diabetic men. Larger studies are needed to confirm the effects of chronic PDE5i on endothelial function.

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“…Adjustment for waist circumference instead of BMI or further adjustment for baseline levels of C-reactive protein, fasting insulin, and HbA1c or exclusion of cases diagnosed during the first 4 years of followup did not alter these associations (Meigs et al, 2004). In the other hand, in diabetes, glycation, tissue oxidation and endothelial function are all abnormal and predisposing to microvascular complications but interrelationships are complex with glycation appearing most direct (Wen et al, 2002). The patients with microalbuminuria, unlike those without it, are characterized by longer course of diabetes, more pronounced lipid exchange disorder, more variable arterial pressure, higher pressure load index, elevated activity of lipid peroxidation (LP) processes and prominent disorder of NO-producing endothelial function.…”

Section: Endothelial Dysfunction and Diabetesmentioning

confidence: 91%