Oxidative stress in diabetes-induced endothelial dysfunction involvement of nitric oxide and protein kinase C

Pricci, Flavia; Leto, Gaetano; Amadio, Lorena; Iacobini, Carla; Cordone, Samantha; Catalano, Stefania; Zicari, Alessandra; Sorcini, Mariella; Mario, U. Di; Pugliese, Giuseppe

doi:10.1016/s0891-5849(03)00401-5

Cited by 82 publications

(70 citation statements)

References 51 publications

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“…STZ-induced diabetes mellitus is associated with the generation of ROS, which causes oxidative damage, (8,37) and ROS formation plays a major role in diabetes-induced endothelial dysfunction. (38,39) In the present study, we found that Xiaokening signifi cantly reduced diabetes-induced elevation of O 2 -. This fi nding suggests that Xiaokening may have the ability to protect arterioles against the cytotoxic action of STZ.…”

Section: Discussionsupporting

confidence: 62%

Xiaokening stimulates endothelial nitric oxide release in diabetic rats

Liu

Wei

et al. 2015

smedj

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INTRODUCTIONDiabetes mellitus is a group of metabolic diseases that is characterised by high blood sugar levels. This occurs either because the body does not produce enough insulin or because cells do not respond to the insulin that is produced. In the past few decades, many studies have shown a clear worldwide increase in the incidence of both type 1 and type 2 diabetes mellitus.(1) Without proper treatment, diabetes mellitus can cause many long-term complications, including cardiovascular disease, chronic renal failure, blindness and nerve damage. Microangiopathy, which is caused by vascular endothelial cell injury and dysfunction, is a fundamental process in diabetes mellitus complications.(2-4) Drug interventions are needed to treat these microvascular complications.Reactive oxygen species (ROS) play a crucial role in the pathogenesis of some diseases (e.g. cancer, cardiovascular disease, diabetes mellitus and infl ammation).(5) The effect of the increased production of free radicals in diabetes mellitus is devastating and well documented.(6-8) Streptozotocin (STZ)-induced diabetic rats are one of the animal models for type 1 diabetes mellitus.(9) In type 1 diabetes mellitus, destruction of the β-cells of the islets of Langerhans causes degranulation or reduction of insulin secretion, but not the total absence of insulin in blood.(10) The cytotoxic action of STZ is associated with the generation of ROS, which causes oxidative tissue damage.(11) There is considerable evidence of the role of altered antioxidant defences (including both nonenzymatic and enzymatic antioxidant systems) and free radicals in the aetiology of diabetes mellitus. (12,13) Many studies have reported that the use of traditional Chinese medicines not only helps to lower serum glucose, but also helps to inhibit the development of diabetic complications. ( 14,15) Our previous research, which was conducted on umbilical vein endothelial cells (ECV-304), found that Xiaokening effectively reduces cellular injury and proliferation inhibition resulting from high glucose serum levels. (16,17) In other words, Xiaokening was found to have protective effects for endothelial cells and the ability to improve cell propagation. These fi ndings indicate that Xiaokening has a positive effect on endothelial cells in vitro. However, there is little information on the effect of Xiaokening on endothelial cells within vessels. As the effect of Xiaokening on diabetic arterioles has not been reported, the aim of the present study was to explore its effect on the mesenteric arteriolar endothelial cell function of diabetic rats and the underlying mechanism. METHODSSTZ and 2,3-diaminonaphthalene (DAN) were purchased from Sigma Chemical Company, MO, USA. The STZ was dissolved in a solution of cold citrate buffer (0.1 M, pH 4.5). The DAN was dissolved in methanol. The STZ and DAN solutions used in the present study were freshly dissolved and shielded from light. Antibody for endothelial nitric oxide synthase (eNOS) was purchased from Santa Cruz Biotechnology, TX, USA....

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Section: Discussionsupporting

confidence: 62%

Xiaokening stimulates endothelial nitric oxide release in diabetic rats

Liu

Wei

et al. 2015

smedj

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“…Mesangial cell ROS levels. ROS levels were assessed by evaluating formation of the intracellular trapped fluorescent compound resulting from the oxidation of 5-(and-6)-chloromethyl-2Ј,7Ј-dichlorodihydrofluorescein diacetate (CM-H 2 DCFDA) (Molecular Probes, Eugene, OR) by several ROS, including H 2 O 2 (28). Briefly, cells were incubated with 5 mol/l CM-H 2 DCFDA in serum-free medium for 30 min at 37°C, fixed in 2% paraformaldehyde, and observed under a fluorescence microscope (Zeiss-Axioplan 2; Carl Zeiss Italy, Arese, Milan, Italy) at 488-nm excitation and 530-nm emission.…”

Section: Renal/mesangial Ecm Rage and P66mentioning

confidence: 99%

Deletion of p66Shc Longevity Gene Protects Against Experimental Diabetic Glomerulopathy by Preventing Diabetes-Induced Oxidative Stress

et al. 2006

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p66Shc regulates both steady-state and environmental stress-dependent reactive oxygen species (ROS) generation. Its deletion was shown to confer resistance to oxidative stress and protect mice from aging-associated vascular disease. This study was aimed at verifying the hypothesis that p66Shc deletion also protects from diabetic glomerulopathy by reducing oxidative stress. Streptozotocin-induced diabetic p66Shc knockout (KO) mice showed less marked changes in renal function and structure, as indicated by the significantly lower levels of proteinuria, albuminuria, glomerular sclerosis index, and glomerular and mesangial areas. Glomerular content of fibronectin and collagen IV was also lower in diabetic KO versus wild-type mice, whereas apoptosis was detected only in diabetic wild-type mice. Serum and renal tissue advanced glycation end products and plasma isoprostane 8-epi-prostaglandin F2␣ levels and activation of nuclear factor B (NF-B) were also lower in diabetic KO than in wild-type mice. Mesangial cells from KO mice grown under high-glucose conditions showed lower cell death rate, matrix production, ROS levels, and activation of NF-B than those from wild-type mice. These data support a role for oxidative stress in the pathogenesis of diabetic glomerulopathy and indicate that p66Shc is involved in the molecular mechanism(s) underlying diabetes-induced oxidative stress and oxidant-dependent renal injury.

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“…Previous studies have shown that the gp91 phox -containing NAD(P)H oxidase is expressed in vascular endothelial cells (4,34). Furthermore, ANG II induces synthesis and release of a number of very active compounds (18,23,31,23,49). It may be that the increased superoxide observed in the inner and outer nuclear layers after ANG II is the result of some of these compounds.…”

Section: Discussionmentioning

confidence: 99%

“…This occurs in diabetic retinopathy (30). There is growing evidence that oxygen free radicals are present in excess in diabetic retinas (19,26,35,36) and in vascular endothelial cells (49). Oxygen free radicals are toxic to tissue because of their high reactivity and ability to form covalent bonds nonenzymatically.…”

Section: Discussionmentioning

confidence: 99%

Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis

Chen¹,

Guo²,

Edwards³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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We studied whether angiotensin II (ANG II) via superoxide may contribute to retinal leukostasis and thus to the pathogenesis of retinopathies. We studied: 1) whether intravitreal ANG II induces retinal leukostasis that is altered by antioxidants or by apocynin, a NAD(P)H oxidase inhibitor and 2) whether retinal leukostasis induced by diabetes in rats is also altered by these treatments. Rats were injected intravitreally with ANG II (20 g in 2 l), and divided into the following three groups: 1) untreated; 2) treated with tempol doses (ϳ3 mM/day) and N-acetylcysteine (NAC; ϳ1 g⅐ kg Ϫ1 ⅐ day Ϫ1 ); and 3) treated with apocynin (ϳ2 mM/day), both in the drinking water. Rats with streptozotocin-induced diabetes were similarly treated. Leukostasis was evaluated 48 h after ANG II or 2 wk after diabetes induction. ANG II increased retinal leukostasis from 0.3 Ϯ 0.5 to 3.7 Ϯ 0.4 leukocytes/ mm 2 (P Ͻ 0.01), and these changes were markedly decreased by treatment with tempol ϩ NAC or apocynin, and also by a blocking antibody against vascular endothelial growth factor given intravitreally (P Ͻ 0.01). In addition, incubation of dihydroethidium-loaded retina sections with ANG II caused marked increase in superoxide formation. Compared with normal controls, retinal leukostasis in diabetic rats markedly increased from 0.2 Ϯ 0.3 to 3.8 Ϯ 0.1 leukocytes/mm 2 (P Ͻ 0.01). Diabetic retinal leukostasis was also decreased by treatment with tempol-NAC and normalized by apocynin. Thus increases in intravitreal ANG II can induce retinal leukostasis, which appears to be mediated via increasing superoxide generation by NAD(P)H oxidase, and by VEGF. The activity of NAD(P)H oxidase is required for leukostasis to occur in the diabetic retina.renin-angiotensin system; angiotensin ii; angiotensin receptor antagonists; diabetes; retinal leukostasis; NAD(P)H oxidase superoxide; vascular endothelial growth factor DIABETIC RETINOPATHY is a major cause of blindness (2, 3) that is characterized by progressive alterations in the retinal microvasculature, manifested by areas of nonperfusion, increased permeability, leaky microaneurysms, and pathological angiogenesis. Two sets of observations suggest that the reninangiotensin system (RAS) may contribute to the pathogenesis of diabetic retinopathy. First, the components of the RAS are present in the eye, and intraocular and serum levels of ANG II, renin, and angiotensin-converting enzyme (ACE) reportedly correlate significantly with the severity of retinopathy (10, 16 -18, 52, 56). Second, ACE inhibitors (ACEi) reportedly arrest or delay progressive breakdown of the blood-retina barrier in normotensive insulin-dependent diabetic patients with nephropathy and have favorable effects on normotensive patients with insulin-dependent diabetic retinopathy (21). These finding suggest the possibility that ANG II acts as an endocrine/paracrine factor and thereby influences the development of diabetic retinopathy, as proposed by some investigators (59).Recent evidence suggests that leukocytes may be involved in the ...

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Oxidative stress in diabetes-induced endothelial dysfunction involvement of nitric oxide and protein kinase C

Cited by 82 publications

References 51 publications

Xiaokening stimulates endothelial nitric oxide release in diabetic rats

Xiaokening stimulates endothelial nitric oxide release in diabetic rats

Deletion of p66Shc Longevity Gene Protects Against Experimental Diabetic Glomerulopathy by Preventing Diabetes-Induced Oxidative Stress

Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis

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