NADPH oxidase inhibitor, apocynin, restores the impaired endothelial‐dependent and ‐independent responses and scavenges superoxide anion in rats with type 2 diabetes complicated by NO dysfunction

Hayashi, Toshio; Juliet, Packiasamy A.R.; Kano-Hayashi, Hatsuyo; Tsunekawa, Taku; Dingqunfang, D.; Sumi, Daigo; Matsui-Hirai, Hisako; Fukatsu, Atsushi; Iguchi, Akihisa

doi:10.1111/j.1463-1326.2004.00393.x

Cited by 60 publications

(40 citation statements)

References 43 publications

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“…The impairment of the acetylcholine-induced vascular relaxation observed in disease conditions has been postulated to be due to a decrease in the bioavailability of NO, in turn caused by an increased generation of reactive oxygen species. [23][24][25] The present data suggest that ACh-induced endothelium-dependent aortic relaxation is impaired by STZ-induced diabetes only in male mice, not in female ones. Likewise, we found that ACh-stimulated NO x production was decreased by diabetes in aortas from male mice, but not in those from female ones (Fig.…”

Section: Discussionmentioning

confidence: 67%

Gender Differences in Vascular Reactivity of Aortas from Streptozotocin-Induced Diabetic Mice

Takenouchi

Kobayashi

Taguchi

et al. 2010

Biological & Pharmaceutical Bulletin

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Diabetes mellitus is a syndrome of disordered metabolism, usually due to a combination of hereditary and environmental causes, resulting in abnormally high blood glucose levels. The two most common forms of diabetes are due to either a diminished production of insulin (type 1) or a diminished response to insulin (type 2). Diabetes is a risk factor in the development of both macro-and microvascular diseases. [1][2][3] Indeed, it increases the incidence of ischemic heart disease, cerebral ischemia, and atherosclerosis, conditions in which endothelial dysfunction plays a role in pathogenesis. One of the most important functions of the endothelium is the production of nitric oxide (NO) in response to various hormonal, mechanical, and chemical stimuli. NO has a variety of effects, including the induction of vascular relaxation. In patients with either type 1 or type 2 diabetes, the forearm blood-flow (dilator) responses to acetylcholine (ACh) are reduced, suggesting endothelial dysfunction. 4,5) In streptozotocin (STZ)-induced diabetic rats or mice, which are models of type 1 diabetes, the endothelium-dependent relaxation induced by ACh is impaired, and reactive oxygen species and polyol products have been suggested to be involved in this impairment.6-9) Moreover, there is evidence that endothelial function is impaired in patients with diabetes mellitus 10,11) in a manner similar to that seen in STZ-treated animals. Thus, STZ-induced diabetic rats and mice may provide models for studies of the underlying causes of endothelial-cell damage in diabetes mellitus, and a means of assessing the contribution of diabetes mellitus to cardiovascular disease states.Gender differences in blood pressure 12) and vascular reactivity [13][14][15][16][17] have been reported in rats and mice. Although in the general (non-diabetic) population, cardiovascular diseases are more frequent in men than in premenopausal women, 18,19) diabetes may produce a greater impairment in the female cardiovascular system, with the result that the above difference between men and premenopausal women disappears in diabetic patients. 20) Although some studies have been carried out on the effects of exogenous sex hormones in diabetes, few studies have compared the influence of diabetes on vascular reactivity between males and females.Against this background, we decided to assess whether there are gender differences in the effects of type 1 diabetes on the endothelium-dependent vascular relaxations to various stimuli. For this, we employed aortas isolated from STZ-induced diabetic mice. Although there have been many reports that male diabetic-model mice or rats exhibit endothelial dysfunction, little is known about gender differences in endothelial function in diabetes, particularly in murine models. That was our rationale for investigating gender differences in vascular reactivity in the aorta using STZ-induced type 1 diabetic-model mice. MATERIALS AND METHODSReagents STZ, clonidine hydrochloride, insulin from porcine pancreas, norepinephrine (NE), and N w -...

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Section: Discussionmentioning

confidence: 67%

Gender Differences in Vascular Reactivity of Aortas from Streptozotocin-Induced Diabetic Mice

Takenouchi

Kobayashi

Taguchi

et al. 2010

Biological & Pharmaceutical Bulletin

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“…This was validated in principle in vivo after chronic NADPH oxidase inhibition in db/db mice. A role for NADPH oxidase has previously been suggested in the development of diabetic cardiovascular and renal complications (33,49). Blockade of NADPH oxidase over 12 weeks of diabetes significantly decreased but did not completely normalize urinary albumin excretion and podocyte depletion.…”

Section: Discussionmentioning

confidence: 99%

Glucose-Induced Reactive Oxygen Species Cause Apoptosis of Podocytes and Podocyte Depletion at the Onset of Diabetic Nephropathy

et al. 2006

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Diabetic nephropathy is the most common cause of endstage renal disease in the U.S. Recent studies demonstrate that loss of podocytes is an early feature of diabetic nephropathy that predicts its progressive course. Cause and consequences of podocyte loss during early diabetic nephropathy remain poorly understood. Here, we demonstrate that podocyte apoptosis increased sharply with onset of hyperglycemia in Ins2Akita (Akita) mice with type 1 diabetes and Lepr db/db (db/db) mice with obesity and type 2 diabetes. Podocyte apoptosis coincided with the onset of urinary albumin excretion (UAE) and preceded significant losses of podocytes in Akita (37% reduction) and db/db (27% reduction) mice. Increased extracellular glucose (30 mmol/l) rapidly stimulated generation of intracellular reactive oxygen species (ROS) through NADPH oxidase and mitochondrial pathways and led to activation of proapoptotic p38 mitogen-activated protein kinase and caspase 3 and to apoptosis of conditionally immortalized podocytes in vitro. Chronic inhibition of NADPH oxidase prevented podocyte apoptosis and ameliorated podocyte depletion, UAE, and mesangial matrix expansion in db/db mice. In conclusion, our results demonstrate for the first time that glucose-induced ROS production initiates podocyte apoptosis and podocyte depletion in vitro and in vivo and suggest that podocyte apoptosis/depletion represents a novel early pathomechanism(s) leading to diabetic nephropathy in murine type 1 and type 2 diabetic models. Diabetes 55: [225][226][227][228][229][230][231][232][233] 2006

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“…Recently, apocynin was proposed as an antioxidant in cultured endothelial and vascular smooth muscle cells but not as an inhibitor of NOX (25). Earlier reports, however, verified that apocynin decreases NADPH-stimulated O 2 Ϫ generation in the vasculature (9,18,20,22,28,32,54), where apocynin may be activated by peroxidases in vascular cells instead of MPOs (55,56). Since there are abundant cell types in blood and in vascular wall, including granulocyte, MPOs may be present in the vessel wall (56).…”

Section: Discussionmentioning

confidence: 99%

“…Apocynin inhibits the translocation of cytoplasmic units and thereafter blocks the assembly of cytosolic units and NOX (22,40,56). This compound requires an activation by myeloperoxidases (MPOs), which are generally expressed in the granulocyte but not in the vascular cell (25,53).…”

Section: Discussionmentioning

confidence: 99%

NADPH oxidase has a directional response to shear stress

Godbole¹,

Lu²,

Guo³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Godbole AS, Lu X, Guo X, Kassab GS. NADPH oxidase has a directional response to shear stress. Am J Physiol Heart Circ Physiol 296: H152-H158, 2009. First published November 14, 2008 doi:10.1152/ajpheart.01251.2007.-Vessel regions with predilection to atherosclerosis have negative wall shear stress due to flow reversal. The flow reversal causes the production of superoxides (O 2 Ϫ ), which scavenge nitric oxide (NO), leading to a decrease in NO bioavailability and endothelial dysfunction. Here, we implicate NADPH oxidase as the primary source of O 2 Ϫ during full flow reversal. Nitrite production and the degree of vasodilation were measured in 46 porcine common femoral arteries in an ex vivo system. Nitrite production and vasodilation were determined before and after the inhibition of NADPH oxidase, xanthine oxidase, or mitochondrial oxidase. NADPH oxidase inhibition with gp91ds-tat or apocynin restored nitrite production and vasodilation during reverse flow. Xanthine oxidase inhibition increased nitrite production at the highest flow rate, whereas mitochondrial oxidase inhibition had no effect. These findings suggest that the NADPH oxidase system can respond to directional changes of flow and is activated to generate O 2 Ϫ during reverse flow in a dose-dependent fashion. These findings have important clinical implications for oxidative balance and NO bioavailability in regions of flow reversal in a normal and compromised cardiovascular system. superoxide; nitric oxide; oxidative balance; reduced nicotinamide adenine dinucleotide phosphate NITRIC OXIDE (NO) is released by endothelial cells to regulate blood vessel diameter acutely as well as to maintain long-term homeostatic conditions of the vessel wall (4,30). NO is produced in the endothelium from L-arginine by the enzyme endothelial NO synthase (eNOS) (4, 41) and is released in response to endothelial shear stress and other stimuli such as acetylcholine (4). Wall shear stress (WSS) has also been found to regulate the activity and expression of eNOS (34,40).Oscillatory and reverse WSS have negative effects on the endothelium due to superoxide (O 2 Ϫ ) production (14, 27, 28, 36, 52). It has been found that reverse flow in blood vessels causes reduced NO due to increased O 2 Ϫ production (36). Since NO is atheroprotective, regions of oscillatory and reverse WSS are more prone to atherosclerosis. Regions near branch points and curved vessels produce near-wall reverse flow (15,16).O 2 Ϫ can quickly inactivate NO, causing reduced NO bioavailability and endothelial dysfunction (9, 33). This endothelial dysfunction is implicated in atherosclerosis, hypertension, and heart failure (9,13,14,18,21). Reduced NO in the vessel wall impairs endothelium-dependent vasodilation, decreases inhibition of platelet and leukocyte adhesion, and is linked to the development of intimal hyperplasia (4, 21, 51). Our group has previously shown that NO production is reduced during reverse flow and that the addition of Tempol (an O 2 Ϫ scavenger) restored NO production in reverse flow to...

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NADPH oxidase inhibitor, apocynin, restores the impaired endothelial‐dependent and ‐independent responses and scavenges superoxide anion in rats with type 2 diabetes complicated by NO dysfunction

Abstract: Apocynin restores the impairment of endothelial and non-endothelial function in diabetic angiopathy in OLETF without changing plasma glucose and lipid levels. NO and O(2) (-) may play a role in this process by decreasing TNF-alpha levels.

Cited by 60 publications

References 43 publications

Gender Differences in Vascular Reactivity of Aortas from Streptozotocin-Induced Diabetic Mice

Gender Differences in Vascular Reactivity of Aortas from Streptozotocin-Induced Diabetic Mice

Glucose-Induced Reactive Oxygen Species Cause Apoptosis of Podocytes and Podocyte Depletion at the Onset of Diabetic Nephropathy

NADPH oxidase has a directional response to shear stress

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