Complex Inhibitory Effects of Nitric Oxide on Autophagy

Sarkar, Sovan; Korolchuk, Viktor I.; Renna, Maurizio; Imarisio, Sara; Fleming, Angeleen; Williams, Andrea; Garcı́a-Arencibia, Moisés; Rose, Claudia; Luo, Shouqing; Underwood, Benjamin R.; Kroemer, Guido; O’Kane, Cahir J.; Rubinsztein, David C.

doi:10.1016/j.molcel.2011.04.029

Cited by 352 publications

(330 citation statements)

References 54 publications

(67 reference statements)

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“…Nitric oxide inhibits autophagy via suppression of MAPK8/JNK1 (mitogen-activated protein kinase 8) and BCL2 (B-cell CLL/lymphoma 2) phosphorylation, which subsequently strengthens the BCL2-BECN1 interaction and prevents binding between PIK3C3/ Vps34 and BECN1. 42,43 However, direct inhibition of NOS2 may result in cardiomyocyte atrophy and reduced contractility. 44 Interestingly, co-inhibition of autophagy and reactive oxygen species formation protects CT (catalase) transgenic mice, namely FVB mice, against lipopolysaccharide (LPS)-induced contractile dysfunction.…”

Section: Heartmentioning

confidence: 99%

Autophagy in sepsis: Degradation into exhaustion?

Wong

et al. 2016

Autophagy

118

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Autophagy is one of the innate immune defense mechanisms against microbial challenges. Previous in vitro and in vivo models of sepsis demonstrated that autophagy was activated initially in sepsis, followed by a subsequent phase of impairment. Autophagy modulation appears to be protective against multiple organ injuries in these murine sepsis models. This is achieved in part by preventing apoptosis, maintaining a balance between the productions of pro-and anti-inflammatory cytokines, and preserving mitochondrial functions. This article aims to discuss the role of autophagy in sepsis and the therapeutic potential of autophagy enhancers.

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Section: Heartmentioning

confidence: 99%

Autophagy in sepsis: Degradation into exhaustion?

Wong

et al. 2016

Autophagy

118

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Section: Autophagy In Glial Cellsmentioning

confidence: 99%

“…mTOR in the astrocyte may play a protective role in ischemia via its downstream kinase S6K1 [81] . mTOR can also regulate the stability of iNOS mRNA in astrocytes, reducing the neurotoxic effect of NO which impairs autophagy by disrupting the BECN1 complex and activates mTORC1 [82][83][84] .OPCs are indispensable during oligodendrocyte differentiation and myelin remyelination; they are activated for remyelination in MS lesions [85,86] . They also play an important role in MS pathogenesis by modulating immune activity in the CNS.…”

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confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively infl uences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Infl ammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-infl ammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinfl ammation associated with the pathogenesis of MS. Keywords: autophagy; multiple sclerosis; neuro-infl ammation ·Review· IntroductionAutophagy, a lysosome-dependent degradation pathway, contributes to maintaining cellular homeostasis. Clearance of long-lived proteins, unnecessary organelles, and aggregate-prone proteins is mainly executed by autophagy for recycling cellular materials [1] . There are three subtypes of autophagy, macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy. Macroautophagy is the major type for selective degradation of protein aggregates or misfolded proteins. The ubiquitin-labeled proteins are recognized by autophagy receptors, such as p62, neighbor of BRCA1 gene 1 (NBR1), and NIP3-like protein X (NIX), to form autophagosomes that then fuse with lysosomes for degradation. Many autophagy-related genes function during this process, such as Unc51-like kinase (ULK1) and autophagy-related gene (ATG) 5. Mammalian target of rapamycin (mTOR) represses autophagy by regulating ULK1 phosphorylation, while AMPK activates this process.CMA mediates the degradation of large molecular-weight proteins containing the KFERQ motif recognized by heat shock cognate protein of 70 kDa (HSC70). The substrate is then escorted to lysosome-associated membrane protein 2 (LAMP2A) for lysosomal degradation. Mitophagy is responsible for the degradation of damaged mitochondria.Parkin and PINK1 play critical roles in this process [2] . More Neurosci Bull August 1, 2015, 31(4): 435-444 436 attention has been paid to autophagy in the path...

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“…Some evidence suggests that in mammalian cultured cells NO, a free radical, inhibits autophagy by nitrosylation of c-Jun N-terminal kinase 1. This ultimately leads to the disruption of the Beclin/1-hVps34 complex, which is necessary during autophagosome formation (Sarkar et al, 2011). At first, these findings might seem in direct contrast to some of the reports discussed above.…”

Section: Perspectivementioning

confidence: 71%

The effects of resveratrol on aging vessels

Díaz

Degens

Vanhees

et al. 2016

Experimental Gerontology

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Aging is a major risk factor for the development of cardiovascular disease. Despite a significant reduction in the mortality and morbidity rates over the last decade, the socio-economic burden of cardiovascular disease is still substantial. Consequently, there is a considerable need for alternative strategies, such as nutraceutical supplementation, that delay the functional vascular decline present in the elderly.Compromised autophagy and oxidative stress (OS) are considered major causes of the age-related endothelial dysfunction. OS reduces the bioavailability of nitric oxide (NO), which has been associated with hypertension, arteriosclerosis and a reduced vasodilatory response. High levels of free radicals and the low bioavailability of NO lead to a positive feedback loop of further OS, organelle damage, poor repair and endothelial dysfunction. Here we draw attention to the relationship between OS and autophagy in the aged vasculature. We have reviewed the published literature and provided arguments that support that treatment with resveratrol stimulates autophagy and thereby has the potential to restore oxidative balance in the endothelium, which indicates that treatment with resveratrol might have therapeutic potential to restore endothelial function in the elderly.

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Complex Inhibitory Effects of Nitric Oxide on Autophagy

Cited by 352 publications

References 54 publications

Autophagy in sepsis: Degradation into exhaustion?

Autophagy in sepsis: Degradation into exhaustion?

Role of autophagy in the pathogenesis of multiple sclerosis

The effects of resveratrol on aging vessels

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