Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L

Dorn, Gerald W.; Kirshenbaum, Lorrie A.

doi:10.1038/onc.2009.53

Cited by 45 publications

(44 citation statements)

References 77 publications

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“…To do this, we used the time-dependent profile of HIF-1␣-Bnip3 signaling as guidance to assess the onset of hypoxic response in MS-1 cells, because the activation of this pathway reflects the hypoxic environment inside cells. 19 As expected, hypoxia-exposed cells had a gradual elevation in the accumulation of HIF-1␣ ( Figure 1C), a transcriptional factor that induces the expression of bnip3 gene. 20 This inducible expression of Bnip3 was evident as early as 6 hours after hypoxia ( Figure 1C), suggesting that hypoxia-induced downstream signaling, including the activation of caspase-3, might be already switched on at this time.…”

Section: Hypoxia-induced Cys Denitrosylation and Activation Of Caspassupporting

confidence: 77%

Nitrite-Mediated S -Nitrosylation of Caspase-3 Prevents Hypoxia-Induced Endothelial Barrier Dysfunction

Lai

Pan

Chang

et al. 2011

Circulation Research

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Rationale: Hypoxia is a significant perturbation that exacerbates endothelial barrier dysfunction, contributing to the disruption of vascular homeostasis and the development of various diseases such as atherosclerosis and metastasis of tumors. To date, it is not known what strategy might be used to counter the effect of hypoxia on endothelial permeability.Objective: This study investigated the role of nitrite in regulating vascular integrity under hypoxic conditions. Methods and Results: We found denitrosylation and the resulting activation of caspase-3 to be critical for hypoxia-induced endothelial permeability. Nitrite treatment led to S-nitrosylation and the inactivation of caspase-3, suppressing the barrier dysfunction of endothelia caused by hypoxia. This process required the conversion of nitrite to bioactive nitric oxide in a nitrite reductase-dependent manner. Using primary human umbilical vein endothelial cells as a model, we showed that in the presence of nitrite, the S-nitrosylated and inactivated form of caspase-3 was unable to cleave ␤-catenin, a key component in the VE-cadherin complex. Therefore, nitrite treatment led to the maintenance of VE-cadherin-mediated adherens junctions under hypoxic conditions. In in vivo experiments using a zebrafish model, nitrite was found to protect blood vessels from hypoxia-induced vascular leakage. Key Words: nitrite Ⅲ NO Ⅲ caspase-3 Ⅲ hypoxia Ⅲ endothelial barrier dysfunction A semipermeable barrier lining along the vasculature, the endothelium regulates the exchange of fluids and solutes between the blood and interstitial space. Dysfunction of the endothelial barrier can lead to problems in the regulation of vascular homeostasis and serious pathological conditions. Increased endothelial permeability may lead to development of various diseases, such as capillary leakage syndrome, 1 atherosclerosis, 2 and tumor metastasis. 3 Because endothelial cells form the first layer in contact with blood, perturbations in blood composition are the main cause of dysfunction of vascular barrier. Hypoxia, one such perturbation, leads to increased endothelial permeability, 4 contributing to the progression of several diseases involving disrupted vascular homeostasis. 5 To date, it remains unclear what governs hypoxia-induced endothelial permeability. It is also not known what strategy might be used to prevent endothelial barrier dysfunction and preserve vascular integrity under hypoxic insult. Conclusions:The constitutive production of nitric oxide (NO) by the endothelial NO synthase (eNOS) has long been regarded as a key regulator of vascular health. 6 Reduced bioavailability of NO contributes to endothelial dysfunction, 7 ultimately leading to the development of various cardiovascular diseases. 8 Interestingly, in response to hypoxia, which induces an increase of vascular permeability, NO production by the endothelium is significantly diminished. 9 One study reported that when a high level of NO donor is artificially delivered to endothelial culture, hypoxia-induced perme...

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Section: Hypoxia-induced Cys Denitrosylation and Activation Of Caspassupporting

confidence: 77%

Nitrite-Mediated S -Nitrosylation of Caspase-3 Prevents Hypoxia-Induced Endothelial Barrier Dysfunction

Lai

Pan

Chang

et al. 2011

Circulation Research

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“…12,13 Furthermore, prenatal application of a caspase-3 inhibitor in the Gq-transgenic background resulted in reduced apoptosis, hemodynamic improvement, and a complete amelioration of mortality. 14 This study, along with others, highlights the critical role of cardiac myocyte death in the progression from cardiac injury to symptomatic heart failure (reviewed in 15 ). Therefore, manipulation of the molecular pathways that regulate myocyte survival could represent important therapeutic strategy to prevent cardiac deterioration.…”

mentioning

confidence: 79%

Multiple Facets of NF-κB in the Heart

Gordon

Shaw

Kirshenbaum

2011

Circulation Research

485

309

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Abstract:The progression from cardiac injury to symptomatic heart failure has been intensely studied over the last decade, and is largely attributable to a loss of functional cardiac myocytes through necrosis, intrinsic and extrinsic apoptosis pathways and autophagy. Therefore, the molecular regulation of these cellular programs has been rigorously investigated in the hopes of identifying a potential cell target that could promote cell survival and/or inhibit cell death to avert, or at least prolong, the degeneration toward symptomatic heart failure. The nuclear factor (NF)-B super family of transcription factors has been implicated in the regulation of immune cell maturation, cell survival, and inflammation in many cell types, including cardiac myocytes. Recent studies have shown that NF-B is cardioprotective during acute hypoxia and reperfusion injury. However, prolonged activation of NF-B appears to be detrimental and promotes heart failure by eliciting signals that trigger chronic inflammation through enhanced elaboration of cytokines including tumor necrosis factor ␣, interleukin-1, and interleukin-6, leading to endoplasmic reticulum stress responses and cell death. The underlying mechanisms that account for the multifaceted and differential outcomes of NF-B on cardiac cell fate are presently unknown. Herein, we posit a novel paradigm in which the timing, duration of activation, and cellular context may explain mechanistically the differential outcomes of NF-B signaling in the heart that may be essential for future development of novel therapeutic interventions designed to target NF-B responses and heart failure following myocardial injury. (Circ Res. 2011;108:1122-1132.)

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“…Известно, например, что экс-прессия гена HIF1A увеличивается при механическом стрессе (Fu-lan et al, 2012), в свою очередь повышенная экспрессия гена HIF1A приводит к активации апоптоза (Park et al, 2014). В работе (Dorn, Kirshenbaum, 2008) показано, что при механическом стрессе, вызванном сдавливанием, активируется транскрипция гена BNIP3. Кроме того, известно, что подавление активности BNIP3 оказывает протективное действие по отношению к апоп-тозу предшественников нервных клеток (Wang et al, 2013).…”

Section: результаты и обсуждениеunclassified

Molecular-genetic mechanisms of the interaction between processes of cell response to mechanical stress and neuronal apoptosis in primary open-angle glaucoma

Saik¹,

Konovalova²,

Деменков³

et al. 2016

Vestn. VOGiS

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Glaucoma is a chronic and progressive disease, which affects more than 60 million people worldwide. Pri mary open-angle glaucoma (POAG) is one of the most common forms of glaucoma. For example, about 2.71 million people in the USA had primary open-angle glaucoma in 2011. Currently POAG is a major cause of irreversible vision loss. In patients with treated open-angle glaucoma the risk of blindness reached to be about 27 %. It is known that the death of optic nerve cells can be triggered by mechanical stress caused by increased intraocular pressure, which induces neuronal apoptosis and is observed in patients with POAG. Currently, there is a large number of scientific publications describing proteins and genes involved in the pathogenesis of POAG, including neuronal apoptosis and the cell response to mechanical stress. However, the molecu lar-genetic mechanisms underlying the pathophysiology of POAG are still poorly understood. Reconstruction of associative networks describing the functional interactions between these genes/proteins, including biochemical reactions, regulatory interactions, transport, etc., requires the use of methods of automated knowledge Глаукома -хроническое, прогрессирующее заболевание, кото-рым страдают более 60 млн человек в мире. Первичная открыто-угольная глаукома (ПОУГ) занимает одно из первых мест по рас-пространенности среди различных форм глаукомы. Например, в 2011 г. эта форма заболевания наблюдалась более чем у 2.7 млн человек в США. В настоящее время ПОУГ является основной при-чиной необратимой потери зрения. У больных с открытоуголь-ной глаукомой риск слепоты достигает 27 %, даже несмотря на проводимое лечение. Известно, что гибель клеток зрительного нерва может быть спровоцирована механическим стрессом, вы-званным повышенным внутриглазным давлением, наблюда ющим-ся при ПОУГ, индуцирующим нейрональный апоптоз. В настоящее время существует огромное количество научных публикаций, описывающих белки и гены, которые участвуют в патогенезе ПОУГ, в том числе в нейрональном апоптозе и клеточном ответе на механический стресс. Тем не менее молекулярно-генетические механизмы, лежащие в основе патофизиологии ПОУГ, до сих пор плохо изучены. Реконструкция ассоциативных генных сетей, опи-сывающих функциональные взаимодействия между этими генами/ белками, включая биохимические реакции, регуляторные взаимо-действия, события транспорта и т. д., требует использования методов автоматизированного извлечения знаний из текстов научных публикаций. В работе проанализированы ассоциативные сети, описывающие молекулярно-генетические взаимодействия между белками и генами, вовлеченными в ответ клетки на меха-нический стресс (ОКМС), нейрональный апоптоз и патогенез ПОУГ. Показано, что гены, ассоциированные с ПОУГ, статистически значимо чаще, чем ожидалось по случайным причинам, представ-лены среди генов, участвующих во взаимодействии между ОКМС и нейрональным апоптозом, что может быть важным фактором, влияющим на гибель ганглиозных ретинальных клеток при ПОУГ. Ключевые

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Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L

Cited by 45 publications

References 77 publications

Nitrite-Mediated S -Nitrosylation of Caspase-3 Prevents Hypoxia-Induced Endothelial Barrier Dysfunction

Nitrite-Mediated S -Nitrosylation of Caspase-3 Prevents Hypoxia-Induced Endothelial Barrier Dysfunction

Multiple Facets of NF-κB in the Heart

Molecular-genetic mechanisms of the interaction between processes of cell response to mechanical stress and neuronal apoptosis in primary open-angle glaucoma

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