Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids

Limbourg, Florian P.; Huang, Zhihong; Plumier, Jean-Christophe; Simoncini, Tommaso; Fujioka, Masayuki; Tuckermann, Jan; Schütz, Günther; Moskowitz, Michael A.; Liao, James K.

doi:10.1172/jci0215481

Cited by 166 publications

(31 citation statements)

References 55 publications

(36 reference statements)

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“…Here we show for the first time that IPostC blocked increases in iNOS and nitrotyrosine expression but not COX-2, suggesting that IPostC has distinct effects on these inflammatory factors. It is well-known that iNOS contributes to neuronal injury and inflammation after stroke (Han et al, 2002; Karabiyikoglu et al, 2003; Limbourg et al, 2002), and that nitrotyrosine is a marker of NO-dependent products derived from iNOS; its expression indicates cell damage and inflammation (Hirabayashi et al, 2000; Martinez-Murillo et al, 2007; Nanetti et al, 2007). We showed that iNOS protein levels increased as early as 1 hour after stroke, maintained high levels for up to 24 hours, and that nitrotyrosine expression was also elevated.…”

Section: Discussionmentioning

confidence: 99%

Tim-3 cell signaling and iNOS are involved in the protective effects of ischemic postconditioning against focal ischemia in rats

2014

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The protective effect of ischemic postconditioning (IPostC) against stroke has been well-established, and the underlying mechanisms are known to involve inhibited-inflammation and free radical production. Nevertheless, how IPostC affects protein expression of iNOS, nitrotyrosine, and COX-2 has not been characterized. In addition, the role of the galectin-9/Tim-3 cell signaling pathway—a novel inflammatory pathway—in IPostC has not been studied. We examined whether iNOS, nitrotyrosine, and COX-2, as well as galectin-9/Tim-3 are involved in the protective effects of IpostC in a rat focal ischemia model. Western blot and confocal immunofluoresent staining results indicate that IPostC significantly inhibited Tim-3 expression, and that galectin-9 expression was also inhibited. In addition, IPostC attenuated production of iNOS and nitrotyrosine, but not COX-2, suggesting that IPostC has distinct effects on these inflammatory factors. Furthermore, the inflammation inhibitor minocycline blocked Tim-3 and iNOS expression induced by stroke. Taken together, we show that the galectin-9/Tim-3 cell signaling pathway is involved in inflammation induced by stroke, and IPostC may reduce infarction by attenuating this novel pathway as well as the inflammatory factors iNOS and nitrotyrosine, but not COX-2.

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Section: Discussionmentioning

confidence: 99%

Tim-3 cell signaling and iNOS are involved in the protective effects of ischemic postconditioning against focal ischemia in rats

2014

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“…Previous studies showed that GCs bind to GR, and activated GR interacts with the p85 regulatory subunit of PI3K and recruits the p110 catalytic subunit in the cytoplasm (Hafezi-Moghadam et al , 2002; Limbourg et al , 2002; Hu et al , 2009). PI3K activates PDK1 by phosphorylating PDK1, which acutely mobilizes to recycling endosomes (RE), where SGK3 and NHE3 are expressed.…”

Section: Discussionmentioning

confidence: 99%

Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na⁺/H⁺exchanger NHE3 by glucocorticoids

Lee

Lin

et al. 2011

MBoC

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“…A beneficial transient activation of cerebral eNOS has been reported to explain the neuroprotective effects of glucocorticoid infusion after stroke. This transient activation, apparently due to a nongenomic glucocorticoid receptor action, is responsible for increased regional cerebral blood flow [58]. The role of cyclic guanosine 3 ′ ,5 ′ -monophosphate (cGMP), a downstream target of nitric oxide signaling, remains unexplored in CS.…”

Section: Pathogenesis Of Hypertension In Cushing's Syndromementioning

confidence: 99%

The hypertension of Cushing's syndrome

Isidori

Graziadio

Paragliola

et al. 2015

Journal of Hypertension

130

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Cushing's syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first ‘Altogether to Beat Cushing's syndrome’ workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushing's syndrome.

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Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids

Cited by 166 publications

References 55 publications

Tim-3 cell signaling and iNOS are involved in the protective effects of ischemic postconditioning against focal ischemia in rats

Tim-3 cell signaling and iNOS are involved in the protective effects of ischemic postconditioning against focal ischemia in rats

Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na⁺/H⁺exchanger NHE3 by glucocorticoids

The hypertension of Cushing's syndrome

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Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids

Cited by 166 publications

References 55 publications

Tim-3 cell signaling and iNOS are involved in the protective effects of ischemic postconditioning against focal ischemia in rats

Tim-3 cell signaling and iNOS are involved in the protective effects of ischemic postconditioning against focal ischemia in rats

Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na+/H+exchanger NHE3 by glucocorticoids

The hypertension of Cushing's syndrome

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Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na⁺/H⁺exchanger NHE3 by glucocorticoids