Early inhibition of HIF-1α with small interfering RNA reduces ischemic–reperfused brain injury in rats

Chen, Chunhua; Hu, Qin; Yan, Junhao; Yang, Xiaomei; Shi, Xiaoming; Lei, Jiliang; Chen, Lin; Huang, Hongyun; Han, Jing‐Yan; Zhang, Junyi; Zhou, Changman

doi:10.1016/j.nbd.2008.12.010

Cited by 103 publications

(71 citation statements)

References 39 publications

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“…Chen et al (9) have reported the early inhibition of the proapoptotic factor HIF-1alpha with siRNA delivered intracerebrally by a commercially available transfection agent that resulted in reduced ischemic-reperfused brain injury in rats. The study suggested that HIF-1alpha and its downstream VEGF and other apoptotic-related proteins such as p53 and Caspase-3 may present an opportunity for the early treatment of ischemic cerebral A B Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Both genetic disruption and pharmacological inhibition of caspases after stroke can reduce ischemic neuronal injury inducing a neuroprotective effect (5)(6)(7)(8). It has been suggested that silencing of apoptotic genes using in vivo RNA interference (RNAi) could be potentially an effective treatment for stroke (5,9) . Moreover, nonviral delivery of siRNA directly to the Central Nervous System (CNS) has been reported to effectively normalize phenotypes in animal models of several neurological diseases (10)(11)(12)(13).…”

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confidence: 99%

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Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing

Al‐Jamal

Gherardini

Bardi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

210

122

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Stroke is the second cause of death worldwide with ischemic stroke accounting for 80% of all stroke insults. Caspase-3 activation contributes to brain tissue loss and downstream biochemical events that lead to programmed cell death after traumatic brain injury. Alleviation of symptoms following ischemic neuronal injury can be potentially achieved by either genetic disruption or pharmacological inhibition of caspases. Here, we studied whether silencing of Caspase-3 using carbon nanotube-mediated in vivo RNA interference (RNAi) could offer a therapeutic opportunity against stroke. Effective delivery of siRNA directly to the CNS has been shown to normalize phenotypes in animal models of several neurological diseases. It is shown here that peri-lesional stereotactic administration of a Caspase-3 siRNA (siCas 3) delivered by functionalized carbon nanotubes (f-CNT) reduced neurodegeneration and promoted functional preservation before and after focal ischemic damage of the rodent motor cortex using an endothelin-1 induced stroke model. These observations illustrate the opportunity offered by carbon nanotube-mediated siRNA delivery and gene silencing of neuronal tissue applicable to a variety of different neuropathological conditions where intervention at well localized brain foci may offer therapeutic and functional benefits.nanomedicine | neurodegenerative | neuroprotection | neurosciences | gene therapy

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing

Al‐Jamal

Gherardini

Bardi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

210

122

View full text Add to dashboard Cite

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“…Similarly, HIF-1␣ was found to mediate ischemic tolerance in the neonatal rat brain (3) as well as in transient (55) and permanent (4) focal cerebral ischemia models. However, in contrast to its protective effects in models of preconditioning or tolerance, ablation of HIF-1 in the brain was associated with neuroprotection to an acute ischemic insult (30) and loss of HIF-1␣ in astrocytes markedly protected neurons from hypoxia-induced neuronal death (8,66). Thus HIF-1␣ activation has been shown to be either beneficial or deleterious in several organ systems depending on the physiological context of the model.…”

Section: Discussionmentioning

confidence: 99%

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Feinman

Deitch

Watkins

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

125

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mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 299: G833-G843, 2010. First published August 5, 2010 doi:10.1152/ajpgi.00065.2010.-Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) are major causes of death in trauma patients. Gut inflammation and loss of gut barrier function as a consequence of splanchnic ischemia-reperfusion (I/R) have been implicated as the initial triggering events that contribute to the development of the systemic inflammatory response, ALI, and MODS. Since hypoxia-inducible factor (HIF-1) is a key regulator of the physiological and pathophysiological response to hypoxia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Utilizing partially HIF-1␣-deficient mice in a global trauma hemorrhagic shock (T/HS) model, we found that HIF-1 activation was necessary for the development of gut injury and that the prevention of gut injury was associated with an abrogation of lung injury. Specifically, in vivo studies demonstrated that partial HIF-1␣ deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1␣ deficiency reduced TNF-␣, IL-1␤, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1␤ mRNA levels were reduced in the lung after T/HS. This study indicates that prolonged intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights. hemorrhagic shock; inflammation; multiple organ dysfunction syndrome; acute lung injury IN PATIENTS SUSTAINING major trauma, the development of the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction (MODS) is a major clinical problem resulting in 50 -80% of all deaths in surgical intensive care units. Since the pathophysiology of this syndrome remains incompletely understood and therapy remains largely supportive (16), studies focusing on the basic biology of traumainduced SIRS, organ injury/dysfunction, and MODS have been major areas of investigation. These mechanistic studies have generated several working hypotheses, one of which is the gut hypothesis of MODS. A key element in the gut hypothesis of MODS is that a splanchnic ischemia-reperfusion (I/R) insult leading to gut inflammation and loss of barrier function is the initial triggering event that turns the gut into the "motor" of MODS (19). However, the exact mechanisms by which gut I/R leads to intestinal injury and how an intestinal ischemic insult is transduced into a systemic inflammatory response remains incomplete. To date, the majority of the molecular and cellular studies investigating shock-induced gut injury and gut-induced MODS have focused pr...

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“…Moreover, hypoxic preconditioning induces stroke tolerance in mice via HIF-1a signaling Wacker et al, 2012). Other studies, however, show that deletion or inhibition of HIF-1a resulted in reduced brain damage after ischemic stroke or hypoxic conditions, suggesting a detrimental role of HIF-1a (Helton et al, 2005;Chen et al, 2009a;Cheng et al, 2014).…”

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confidence: 99%

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

et al. 2014

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Early inhibition of HIF-1α with small interfering RNA reduces ischemic–reperfused brain injury in rats

Cited by 103 publications

References 39 publications

Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing

Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

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