Endoplasmic reticulum stress-mediated inhibition of NSMase2 elevates plasma membrane cholesterol and attenuates NO production in endothelial cells

Chaube, Ruchi; Kallakunta, Vasantha Madhuri; Espey, Michael Graham; McLarty, Ryan; Faccenda, Adam; Ananvoranich, Sirinart; Mutus, Bülent

doi:10.1016/j.bbalip.2011.10.015

Cited by 18 publications

(11 citation statements)

References 52 publications

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“…Neuronal nitric oxide synthase protects the pancreatic beta cells from glucolipotoxicity-induced endoplasmic reticulum stress and apoptosis [29]. Endoplasmic reticulum stress-mediated inhibition of NSMase2 elevates plasma membrane cholesterol and attenuates NO production in endothelial cells [30]. eNOS is negatively regulated by CHOP-10 in the process of postnatal neovascularization [31].…”

Section: Discussionmentioning

confidence: 99%

Baicalin Protects the Cardiomyocytes from ER Stress-Induced Apoptosis: Inhibition of CHOP through Induction of Endothelial Nitric Oxide Synthase

et al. 2014

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Baicalin, the main active ingredient of the Scutellaria root, exerts anti-oxidant and anti-apoptotic effects in cardiovascular diseases. However, the therapeutic mechanism of baicalin remains unknown. Cultured neonatal rat cardiomyocytes were pre-treated with baicalin (0–50 µM) for 24 h, and subsequently treated with tunicamycin (100 ng/ml). Cell viability was detected by MTT assay, and cell damage was determined by LDH release and TUNEL assay. The expression of CHOP, JNK, caspase-3, eNOS was analyzed by western blot. NO was measured by DAF-FM staining. As a result, treatment with baicalin significantly reduced apoptosis induced by ER stress inducer tunicamycin in cardiomyocytes. Molecularly, baicalin ameliorated tunicamycin-induced ER stress by downregulation of CHOP. In addition, baicalin inverted tunicamycin-induced decreases of eNOS mRNA and protein levels, phospho eNOS and NO production through CHOP pathway. However, the protective effects of baicalin were significantly decreased in cardiomyocytes treated with L-NAME, which suppressed activation of nitric oxide synthase. In conclusion, our results implicate that baicalin could protect cardiomyocytes from ER stress-induced apoptosis via CHOP/eNOS/NO pathway, and suggest the therapeutic values of baicalin against ER stress-associated cardiomyocyte apoptosis.

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Section: Discussionmentioning

confidence: 99%

Baicalin Protects the Cardiomyocytes from ER Stress-Induced Apoptosis: Inhibition of CHOP through Induction of Endothelial Nitric Oxide Synthase

et al. 2014

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“…The assay mixture for aSMase contained 0.1 mM acetate buffer (pH 5.8). The activity of nSMase2 was assessed using the Amplex Red Sphingomyelinase Assay Kit as described in previous reports [43]; however, the sample was the IP-purified enzyme (about 5 μg in 100 μl of elution buffer), not the total protein.…”

Section: Methodsmentioning

confidence: 99%

Early activation of nSMase2/ceramide pathway in astrocytes is involved in ischemia-associated neuronal damage via inflammation in rat hippocampi

Huang

Shen

et al. 2013

J Neuroinflammation

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BackgroundCeramide accumulation is considered a contributing factor to neuronal dysfunction and damage. However, the underlying mechanisms that occur following ischemic insult are still unclear.MethodsIn the present study, we established cerebral ischemia models using four-vessel occlusion and oxygen-glucose deprivation methods. The hippocampus neural cells were subjected to immunohistochemistry and immunofluorescence staining for ceramide and neutral sphingomyelinase 2 (nSMase2) levels; immunoprecipitation and immunoblot analysis for nSMase2, receptor for activated C kinase 1 (RACK1), embryonic ectoderm development (EED), p38 mitogen-activated protein kinase (p38MAPK) and phosphorylated p38MAPK expression; SMase assay for nSMase and acid sphingomyelinase (aSMase) activity; real-time reverse transcription polymerase chain reaction for cytokine expression; and Nissl, microtubule-associated protein 2 and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining.ResultsWe found considerable production of ceramide in astrocytes, but not in neurons, during early cerebral ischemia. This was accompanied by the induction of nSMase (but not aSMase) activity in the rat hippocampi. The inhibition of nSMase2 activity effectively reduced ceramide accumulation in astrocytes and alleviated neuronal damage to some extent. Meanwhile, the expression levels of proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6, were found to be upregulated, which may have played an import role in neuronal damage mediated by the nSMase2/ceramide pathway. Although enhanced binding of nSMase2 with RACK1 and EED were also observed after cerebral ischemia, nSMase2 activity was not blocked by the TNF-α receptor inhibitor through RACK1/EED signaling. p38MAPK, but not protein kinase Cζ or protein phosphatase 2B, was able to induce nSMase2 activation after ischemia. p38MAPK can be induced by A2B adenosine receptor (A2BAR) activity.ConclusionsThese results indicate that the inhibition of ceramide production in astrocytes by targeting A2BAR/p38MAPK/nSMase2 signaling may represent a viable approach for attenuating inflammatory responses and neuronal damage after cerebral ischemia.

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“…Vasorelaxation is mediated by the K Ca 3.1 (IK Ca ) and SK Ca ion channels, and NO production derived from ECs. Homocysteine‐induced ER stress impairs NO production, IK Ca and SK Ca channels, as well as NOX‐generated ROS (Chaube et al ., ; Wang et al ., ). Another target of homocysteine is soluble epoxide hydrolase (sEH), an enzyme that hydrolyses epoxyeicosatrienoic acids and attenuates their vasorelaxing and protective effects in ECs.…”

Section: The Mechanisms Of Vascular Injury Induced By Hhcymentioning

confidence: 99%

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Wang

Kong

2017

British J Pharmacology

118

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Endoplasmic reticulum stress-mediated inhibition of NSMase2 elevates plasma membrane cholesterol and attenuates NO production in endothelial cells

Cited by 18 publications

References 52 publications

Baicalin Protects the Cardiomyocytes from ER Stress-Induced Apoptosis: Inhibition of CHOP through Induction of Endothelial Nitric Oxide Synthase

Baicalin Protects the Cardiomyocytes from ER Stress-Induced Apoptosis: Inhibition of CHOP through Induction of Endothelial Nitric Oxide Synthase

Early activation of nSMase2/ceramide pathway in astrocytes is involved in ischemia-associated neuronal damage via inflammation in rat hippocampi

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

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