<i>O</i>-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Lima, Victor Vitorino; Giachini, Fernanda R.; Hardy, David; Webb, R.; Tostes, Rita C.

doi:10.1152/ajpregu.00230.2010

Cited by 47 publications

(42 citation statements)

References 175 publications

(235 reference statements)

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“…As recently reviewed, there are multiple targets that are regulated by O-GlcNAcylation in the vasculature (30). A positive correlation between phosphorylation of the MAPK cascade (ERK1/2 and p38) and nuclear O-GlcNAcylation was observed in fetal human cardiac myocytes exposed to high glucose (14).…”

Section: Discussionmentioning

confidence: 91%

Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

Prakash

Chawla

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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-Obesity is a risk factor for stroke, but the early effects of high-fat diet (HFD) on neurovascular function and ischemic stroke outcomes remain unclear. The goal of this study was to test the hypotheses that HFD beginning early in life 1) impairs neurovascular coupling, 2) causes cerebrovascular dysfunction, and 3) worsens short-term outcomes after cerebral ischemia. Functional hyperemia and parenchymal arteriole (PA) reactivity were measured in rats after 8 wk of HFD. The effect of HFD on basilar artery function after middle cerebral artery occlusion (MCAO) and associated O-GlcNAcylation were assessed. Neuronal cell death, infarct size, hemorrhagic transformation (HT) frequency/severity, and neurological deficit were evaluated after global ischemia and transient MCAO. HFD caused a 10% increase in body weight and doubled adiposity without a change in lipid profile, blood glucose, and blood pressure. Functional hyperemia and PA relaxation were decreased with HFD. Basilar arteries from stroked HFD rats were more sensitive to contractile factors, and acetylcholine-mediated relaxation was impaired. Vascular O-GlcNAcylated protein content was increased with HFD. This group also showed greater mortality rate, infarct volume, HT occurrence rate, and HT severity and poor functional outcome compared with the control diet group. These results indicate that HFD negatively affects neurovascular coupling and cerebrovascular function even in the absence of dyslipidemia. These early cerebrovascular changes may be the cause of greater cerebral injury and poor outcomes of stroke in these animals. cerebral ischemia; high-fat diet; hemorrhagic transformation; neurovascular coupling; vascular dysfunction OBESITY IS an independent risk factor for acute ischemic stroke (AIS) (19,36). An alarming recent report showed that the prevalence of AIS dramatically increased in children and young adults, which positively correlated with increases in risk factors including obesity, lipid disorders, and diabetes (13). Clinical studies also suggest that obesity is an independent predictor of unfavorable functional outcome and mortality in AIS patients treated with tissue plasminogen activator (tPA), the only therapeutic option these patients have (39,40). Given that stroke is the leading cause of disability and that the obesity epidemic is on the rise these clinical and social problems are expected to get worse, and therefore early interventions are necessary. While experimental studies in genetic or diet-induced obesity models have shown increased cerebral infarct size and poor outcomes of stroke (7,25,32,33,41), the early impact of a high-fat diet (HFD) before the development of obesity on AIS injury and functional outcomes is not known.It is known that the brain relies heavily on constant blood flow for proper function. Two important mechanisms that contribute to the regulation of cerebral blood perfusion are autoregulatory behavior of cerebral vessels and functional hyperemia upon increased neuronal activity (11,16,20). HFD can negatively af...

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Section: Discussionmentioning

confidence: 91%

Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

Prakash

Chawla

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Several studies have demonstrated that elevating O-GlcNAc levels induces many of the hallmarks of hypertension, such as increasing reactivity to constrictor stimuli (phenylephrine) and impaired endothelium-dependent vasodilatation (95)(96)(97). The mechanisms that underlie these observations appear to be regulated in part by decreased phosphorylation of Akt (Ser473) and eNOS (Ser1177) (95)(96)(97).…”

Section: O-glcnac As a Regulator Of Cell Survival O-glcnac A Novel mentioning

confidence: 99%

“…The mechanisms that underlie these observations appear to be regulated in part by decreased phosphorylation of Akt (Ser473) and eNOS (Ser1177) (95)(96)(97). Previously, eNOS was shown to be hyper-O-GlcNAcylated in a model of diabetes-induced erectile dysfunction.…”

Section: O-glcnac As a Regulator Of Cell Survival O-glcnac A Novel mentioning

confidence: 99%

The roles ofO-linked β-N-acetylglucosamine in cardiovascular physiology and disease

Zachara

2012

American Journal of Physiology-Heart and Circulatory Physiology

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More than 1,000 proteins of the nucleus, cytoplasm, and mitochondria are dynamically modified by O-linked β- N-acetylglucosamine ( O-GlcNAc), an essential post-translational modification of metazoans. O-GlcNAc, which modifies Ser/Thr residues, is thought to regulate protein function in a manner analogous to protein phosphorylation and, on a subset of proteins, appears to have a reciprocal relationship with phosphorylation. Like phosphorylation, O-GlcNAc levels change dynamically in response to numerous signals including hyperglycemia and cellular injury. Recent data suggests that O-GlcNAc appears to be a key regulator of the cellular stress response, the augmentation of which is protective in models of acute vascular injury, trauma hemorrhage, and ischemia-reperfusion injury. In contrast to these studies, O-GlcNAc has also been implicated in the development of hypertension and type II diabetes, leading to vascular and cardiac dysfunction. Here we summarize the current understanding of the roles of O-GlcNAc in the heart and vasculature.

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“…It plays a crucial role in the vascular function of most organ systems, both in physiological and pathophysiological conditions (17). In the pathological processes responsible for hypertension (18,19), ET peptides and their receptors are involved in the physiological control of systemic blood pressure and body Na homeostasis (20).…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 and type III collagen alterations in the heart of rats following cisplatin-induced toxicity

Huang

Liu

2011

Mol Med Report

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Abstract. Cisplatin-induced heart damage is associated with enzymes and protein alterations. The purpose of this study was to investigate cisplatin-induced alterations in cardiac endothelin (ET)-1 and type III collagen following administration of cisplatin. Male Wistar rats were randomly divided into two groups: a control and a cisplatin group. The cisplatin group received cisplatin intraperitoneally (i.p.) at a single dose of 7 mg/kg on day 6, while the controls were given the same amount of saline via the same route. On day 11, the rats were anesthetized and a thoracotomy was performed on all animals. Immunohistochemical analysis was performed to evaluate the protein expression of ET-1 and type III collagen. Sections were analyzed by digital image analysis. Results showed that the cardiac protein expression of ET-1 and type III collagen was altered following cisplatin-induced toxicity in rats. The expression of ET-1 and type III collagen was significantly increased after cisplatin treatment, supported by integrated optical density, when compared to the control group (P<0.05). The present findings indicate that such alterations may be reflected in abnormal cardiac function. Additionally, the proteins identified in this study may benefit investigations into the mechanisms underlying cisplatin-induced toxicity, thereby providing the necessary evidence for further research. IntroductionCisplatin is a chemotherapeutic agent widely used to treat a variety of solid tumors (1,2). It is also an antineoplastic drug that causes an array of adverse effects on various organs and tissues (3). Nephrotoxicity is one of the major side-effects of cisplatin chemotherapy (4) limiting the promising efficacy of cisplatin (5). Cisplatin-based chemotherapy also has a variety of vascular side-effects (6). Acute administration of cisplatin induces nausea/emesis and diarrhea (7). Chronic cisplatin may induce an enteric neuropathy characterized by changes in myenteric neurons associated with marked gastrointestinal motor dysfunction (7). Dysfunction in immune surveillance during anticancer chemotherapy of patients often causes weakness of the host defense system and a subsequent increase in microbial infections (8).Cisplatin-induced toxicity is known to be involved in the changes of antioxidant enzymes (GST, SOD, CAT, GSH-Px and GSH), serum superoxide dismutase (SOD), glutathione (GSH), malondiethylaldehyde (MDA), nitric oxide (NO) (9) and DNA (2,10). However, little is known about the changes in endothelin (ET)-1 and type III collagen expression in the heart following cisplatin-induced toxicity.The present study used immunohistochemical analysis to evaluate the expression of ET-1 and type III collagen in the heart, and to determine whether or not the protein expression is altered with cisplatin-induced toxicity. Materials and methodsAnimals and study design. Sixteen healthy adult male Wistar rats, weighing 210-250 g, were used in this study. The animals were housed individually in stainless-steel wire-bottomed cages in an air-conditione...

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O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Cited by 47 publications

References 175 publications

Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

The roles ofO-linked β-N-acetylglucosamine in cardiovascular physiology and disease

Endothelin-1 and type III collagen alterations in the heart of rats following cisplatin-induced toxicity

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