Role of AT₁ receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury

Abstract

jective of the present study was to examine the role of the angiotensin II type 1 receptor (AT1-R) in the diabetes-aggravated oxidative stress and brain injury observed in a rat model of combined diabetes and focal cerebral ischemia. Diabetes was induced by an injection of streptozotoxin (STZ; 55 mg/kg iv) at 8 wk of age. Two weeks after the induction of diabetes, some animals received continuous subcutaneous infusion of the AT1-R antagonist candesartan (0.5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) for 14 days. Focal cerebral ischemia, induced by middle cerebral artery occlusion/reperfusion (MCAO), was conducted at 4 wk after STZ injection. Male Sprague-Dawley rats (n ϭ 189) were divided into five groups: normal control, diabetes, MCAO, diabetes ϩ MCAO, and diabetes ϩ MCAO ϩ candesartan. The major observations were that 1) MCAO produced typical cerebral infarction and neurological deficits at 24 h that were accompanied by elevation of NAD(P)H oxidase gp91 phox and p22 phox mRNAs, and lipid hydroperoxide production in the ipsilateral hemisphere; 2) diabetes enhanced NAD(P)H oxidase gp91 phox and p22 phox mRNA expression, potentiated lipid peroxidation, aggravated neurological deficits, and enlarged cerebral infarction; and 3) candesartan reduced the expression of gp91 phox and p22 phox , decreased lipid peroxidation, lessened cerebral infarction, and improved the neurological outcome. We conclude that diabetes exaggerates the oxidative stress, NAD(P)H oxidase induction, and brain injury induced by focal cerebral ischemia. The diabetes-aggravated brain injury involves AT1-Rs. We have shown for the first time that candesartan reduces brain injury in a combined model of diabetes and cerebral ischemia.angiotensin type 1 receptor antagonist IT HAS BEEN ESTABLISHED THAT diabetes is a risk factor for cerebral ischemia, and the relative risk of cerebral ischemia in diabetic patients is approximately twice as much as in patients without diabetes (6,15,28). In addition, diabetes is strongly related to early brain injury and to the poor outcome after cerebral ischemia (10,28,54). Clinical studies on diabetic patients showed that hyperglycemia augments brain lesions associated with cerebral ischemia (29,47). In animal models of cerebral ischemia, hyperglycemic animals suffered greater neurological deficit with extensive brain damage and widespread necrosis than nonhyperglycemic animals (17, 53). One of the mechanisms of diabetes-enhanced brain injury is oxidative stress caused by hyperglycemia (58).Reactive oxygen species-mediated oxidative stress is believed to produce tissue injury in wide variety of diseases, including diabetes (58). Several enzymes, especially NAD(P)H oxidase, are recognized as being potentially able to produce reactive oxygen species during diabetes (31). NAD(P)H oxidase consists of five major subunits: a plasma membrane spanning cytochrome b 558 composed of the large subunit gp91 phox , the smaller p22 phox subunit, and three cytosolic compounds (p47 phox , p67 phox , and p40 phox ) (19,30). When cells are stimulated, th...

The Long-Term Effect of Angiotensin II Type 1a Receptor Deficiency on Hypercholesterolemia-Induced Atherosclerosis

“…Ang II was found to activate p47phox via AT1 (30). In addition, ARB was reported to inhibit p22phox mRNA expression caused by mechanical stretching and in patients with diabetes mellitus (31,32). We also showed that AT1a deficiency in apoE-KO mice inhibited the expression of p22phox at 60 weeks of age.…”

Losartan improves impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type 1 diabetic rats

“…Support for this latter concept can be found in studies that have shown that stimulation of vascular cells with angiotensin II increases the activity of NAD(P)H oxidase, increases the expression of p47phox and stimulates the production of superoxide anion (Fukui et al, 1997;Griendling et al, 1994;Griendling et al, 2000;Landmesser et al, 2002;. Further, inhibition of AT1R can decrease angiotensin II-induced increases in superoxide anion production by vascular cells (Berry et al, 2000;Kusaka et al, 2004;Zimmerman et al, 2002). Thus, in the present study we tested the hypotheses that angiotensin II could impair eNOS-dependent reactivity of rat cerebral arterioles and that treatment of diabetic rats with an AT1R antagonist (losartan) would alleviate/prevent impaired eNOS-dependent responses of cerebral arterioles via an influence on oxidative stress.…”

NADPH Oxidase Mediates Hypersomnolence and Brain Oxidative Injury in a Murine Model of Sleep Apnea

“…NADPH oxidase-dependent production of superoxide radical (O 2 Ϫ ·) has been identified as a major contributor to oxidative injury in the brain under conditions of both inflammation and severe hypoxia/reperfusion injury (13)(14)(15)(16). Moreover, NADPH oxidase has been implicated in oxidative neurodegeneration, including Alzheimer's disease (17,18), and in dopaminergic neuronal injury in murine models of Parkinson's disease (19)(20)(21).…”