Targeting eNOS and beyond: emerging heterogeneity of the role of endothelial Rho proteins in stroke protection

Sawada, Naoki; Liao, James K.

doi:10.1586/ern.09.70

Cited by 32 publications

(28 citation statements)

References 154 publications

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“…In addition to the BBB, brain ECs also regulate cerebral blood flow and vasoreactivity (33), as well as cerebrovascular inflammation and thrombosis (9). Although the current work underscores the importance of KLF2 in BBB regulation, we recognize that additional mechanisms may be operative in the observed stroke phenotype.…”

Section: Discussionmentioning

confidence: 99%

Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function

Shi

Sheng

Zhang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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During an ischemic stroke normal brain endothelial function is perturbed, resulting in blood brain barrier (BBB) breakdown with subsequent infiltration of activated inflammatory blood cells, ultimately leading to neuronal cell death. Kruppel-like factor 2 (KLF2) is regulated by flow, is highly expressed in vascular endothelial cells (ECs), and serves as a key molecular switch regulating endothelial function and promoting vascular health. In this study we sought to determine the role of KLF2 in cerebrovascular function and the pathogenesis of ischemic stroke. Transient middle cerebral artery occlusion was performed in KLF2-deficient (KLF2(-/-)), KLF2 overexpressing (KLF2(tg)), and control mice, and stroke volume was analyzed. BBB function was assessed in vivo by real-time neuroimaging using positron emission tomography and Evan's blue dye assay. KLF2(-/-) mice exhibited significantly larger strokes and impairment in BBB function. In contrast, KLF2(tg) mice were protected against ischemic stroke and demonstrated preserved BBB function. In concordance, gain- and loss-of-function studies in primary brain microvascular ECs using transwell assays revealed KLF2 to be BBB protective. Mechanistically, KLF2 was demonstrated, both in vitro and in vivo, to regulate the critical BBB tight junction factor occludin. These data are first to identify endothelial KLF2 as a key regulator of the BBB and a novel neuroprotective factor in ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function

Shi

Sheng

Zhang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…However, nitric oxide is also an important second messenger especially in endothelial and neuronal cells. Indeed, increase in NO production through the stimulation of eNOS activity has been reported to protect against stroke through a wide range of cellular effects, including vasodilation, antithrombotic, anti-inflammatory and anti-proliferative activities [41]. One of the striking clinical symptoms in MELAS is the occurrence of stroke-like episodes, which is supposed to be linked to the NO metabolism [11].…”

Section: Discussionmentioning

confidence: 99%

Metabolically induced heteroplasmy shifting and l-arginine treatment reduce the energetic defect in a neuronal-like model of MELAS

Desquiret-Dumas¹,

Guéguen²,

Barth³

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The m.3243A>G variant in the mitochondrial tRNALeu (UUR) gene is a common mitochondrial DNA (mtDNA) mutation. Phenotypic manifestations depend mainly on the heteroplasmy, i.e. the ratio of mutant to normal mtDNA copies. A high percentage of mutant mtDNA is associated with a severe, life-threatening neurological syndrome known as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). MELAS is described as a neurovascular disorder primarily affecting the brain and blood vessels, but the pathophysiology of the disease is poorly understood. We developed a series of cybrid cell lines at two different mutant loads: 70% and 100% in the nuclear background of a neuroblastoma cell line (SH-SY5Y). We investigated the impact of the mutation on the metabolism and mitochondrial respiratory chain activity of the cybrids. The m.3243A>G mitochondrial mutation induced a metabolic switch towards glycolysis in the neuronal cells and produced severe defects in respiratory chain assembly and activity. We used two strategies to compensate for the biochemical defects in the mutant cells: one consisted of lowering the glucose content in the culture medium, and the other involved the addition of L-arginine. The reduction of glucose significantly shifted the 100% mutant cells towards the wild-type, reaching a 90% mutant level and restoring respiratory chain complex assembly. The addition of L-arginine, a nitric oxide (NO) donor, improved complex I activity in the mutant cells in which the defective NO metabolism had led to a relative shortage of NO. Thus, metabolically induced heteroplasmy shifting and L-arginine therapy may constitute promising therapeutic strategies against MELAS.

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“…37,38 It is also reported that the modulation of eNOS mRNA stability plays an important role in eNOS regulation, especially in response to pathological stimuli, including oxidized LDL and cytokine tumor necrosis factor-␣. 39 Importantly, eNOS mRNA stability was found to be regulated by statins, 40 which are widely used in clinical cardiovascular and cerebrovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

A Pentapeptide Monocyte Locomotion Inhibitory Factor Protects Brain Ischemia Injury by Targeting the eEF1A1/Endothelial Nitric Oxide Synthase Pathway

Zhang

Fan

Liu

et al. 2012

Stroke

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Background and Purpose-Ischemic stroke is a major cause of death worldwide but lacks viable treatment or treatment targets. Monocyte locomotion inhibitory factor (MLIF) is a small heat-stable pentapeptide produced by Entamoeba histolytica in axenic culture, which is supposed to protect the brain from ischemic injury; the mechanism, however, remains unknown. In this study, we further investigated the mechanism underlying the protective role of MLIF in brain ischemia. Methods-A middle cerebral artery occlusion model in rats was used for detecting the effect of MLIF in the brain ischemia in vivo. To identify targets of MLIF in brain endothelial cells, we performed immunoprecipitation of biotin-conjugated MLIF and mass spectrometry. Results-MLIF can protect the brain from ischemic injury in vivo, yielding decreased ischemic volume, prolonged survival, and improved neurological outcome. In vitro studies showed that MLIF displayed protective effects through inhibition of expression of pathological inflammatory adhesion molecules and enhancing endothelial nitric oxide synthase expression and nitric oxide release in the cerebrovascular endothelium. The target screening experiments demonstrated binding of MLIF to the ribosomal protein translation elongation factor eEF1A1. MLIF enhanced endothelial nitric oxide synthase expression through stabilization of endothelial nitric oxide synthase mRNA, and eEF1A1 was shown to be necessary for this enhanced expression. Knockdown of eEF1A1 or inhibition of endothelial nitric oxide synthase attenuated MLIF-mediated inhibition of adhesion molecule expression. Conclusions-In this study, we identified a new potential pharmacologically targetable mechanism underlying MLIF's protective effects in brain ischemia through the eEF1A1/endothelial nitric oxide synthase pathway. (Stroke. 2012;43:2764-2773.)

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Targeting eNOS and beyond: emerging heterogeneity of the role of endothelial Rho proteins in stroke protection

Cited by 32 publications

References 154 publications

Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function

Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function

Metabolically induced heteroplasmy shifting and l-arginine treatment reduce the energetic defect in a neuronal-like model of MELAS

A Pentapeptide Monocyte Locomotion Inhibitory Factor Protects Brain Ischemia Injury by Targeting the eEF1A1/Endothelial Nitric Oxide Synthase Pathway

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