Oxidant treatment causes a dose-dependent phenotype of apoptosis in cultured motoneurons

Kaal, Evert C. A.; Veldman, H.; Sodaar, Peter; Joosten, Elbert A.J.; Bär, P.R.

doi:10.1002/(sici)1097-4547(19981215)54:6<778::aid-jnr5>3.0.co;2-0

Cited by 39 publications

(24 citation statements)

References 24 publications

(39 reference statements)

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“…H 2 O 2 stimulates VSMC proliferation, NADH/NADPH oxidase inhibition reduces Ang II-stimulated hypertrophy, and VSMC treatment with antioxidants induces apoptosis. 18,19 Our findings in human VSMCs support a redox-sensitive growth effect of Ang II. The mechanisms through which ROS mediate growth appear to be linked to activation of ERK5 and p38 MAP kinase, which are redox-sensitive kinases.…”

Section: Discussionsupporting

confidence: 61%

“…6,15Ϫ17 Furthermore, antioxidants inhibit cell growth and trigger apoptosis, which implies that a basal level of oxidant stress is necessary for normal cell growth. 18,19 Vascular tissue is constantly exposed to endogenous and exogenous oxidants, which, if unscavenged, may lead to cellular proliferation. ROS concentrations are increased in atherosclerosis, neointimal formation, and hypertension.…”

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confidence: 99%

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Ang II–Stimulated Superoxide Production Is Mediated via Phospholipase D in Human Vascular Smooth Muscle Cells

1999

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Abstract-Intracellular signaling events that mediate the long-term effects of Ang II in vascular smooth muscle cells are unclear, but oxidative stress may play an important role. This study examined the ability of Ang II to generate reactive oxygen species and investigated the putative role of phospholipase D (PLD)-dependent signaling pathways for its production in human vascular smooth muscle cells. In addition, we assessed whether redox-sensitive pathways influence Ang II-stimulated cell growth. Primary and low-passage cells (passages 1 to 4) derived from resistance arteries of subcutaneous gluteal biopsies from healthy subjects were studied. Key Words: oxidative stress Ⅲ superoxide anions Ⅲ intracellular signaling Ⅲ vascular hypertrophy T he multiple actions of Ang II are mediated via highly complex intracellular signaling pathways that are stimulated after binding of the peptide to its cell-surface receptors. 1 The signaling processes are multiphasic, with distinct temporal characteristics. 2 Ang II-induced activation of phospholipase C characteristically occurs within seconds, resulting in increased intracellular free Ca 2ϩ concentration and rapid vascular contraction, 3,4 whereas activation of signaling pathways mediating protein synthesis and cell growth are delayed, occurring within minutes or hours after Ang II stimulation. 2,5 Although the intracellular signaling events underlying Ang II-induced growth are not completely understood, there is increasing evidence suggesting that generation of reactive oxygen species (ROS), such as superoxide anion (⅐O 2 Ϫ ), hydrogen peroxide (H 2 O 2 ), and the reactive hydroxyl radical (⅐OH), may be fundamental in the mitogenic response to this peptide. 6Ϫ8 The major source of ⅐O 2 Ϫ in cardiovascular cells is NADH/ NADPH oxidase, 9Ϫ12 which transfers electrons from NADH or NADPH to molecular oxygen, producing ⅐O 2 Ϫ . The ⅐O 2 Ϫ that is generated by NADH/NADPH oxidase is converted by superoxide dismutase to H 2 O 2 , which is scavenged by catalase or by peroxidases. 13 ⅐O 2 Ϫ and H 2 O 2 stimulate vascular smooth muscle cell (VSMC) hyperplasia and hypertrophy. 6,9,14 These effects are associated with growth-related events such as intracellular alkalinization, increased intracellular free Ca 2ϩ concentration, MAP kinase activation, and induction of proto-oncogene expression. 6,15Ϫ17 Furthermore, antioxidants inhibit cell growth and trigger apoptosis, which implies that a basal level of oxidant stress is necessary for normal cell growth. 18,19 Vascular tissue is constantly exposed to endogenous and exogenous oxidants, which, if unscavenged, may lead to cellular proliferation. ROS concentrations are increased in atherosclerosis, neointimal formation, and hypertension. 20Ϫ22 In Ang II-induced but not catecholamineinduced hypertension, aortic superoxide is increased, which suggests that Ang II-induced effects in hypertension are mediated in part through oxidative stress. 23,24

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Section: Discussionsupporting

confidence: 61%

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confidence: 99%

Ang II–Stimulated Superoxide Production Is Mediated via Phospholipase D in Human Vascular Smooth Muscle Cells

1999

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“…Despite almost total cell death at 48 h (Ͼ94%), as indicated by nuclear morphology, LDH release was moderate after treatment with STS. A possible explanation for this finding is that apoptosis results in a compaction of the cell membrane without the spillage of cell contents into the culture medium before secondary necrosis (17). All UCB concentrations induced a significant proportion of condensed nuclei with disrupted membrane and a significant increase in LDH release compared with controls within 24 h, consistent with a component of early necrotic cell death.…”

Section: Discussionmentioning

confidence: 76%

“…Hoechst 33342 stains the nuclei of all living and dead cells, while nuclei of cells with damaged cell membranes, as seen in necrosis, are stained by EH. All dying and dead cells eventually lose nuclear and plasma membrane integrity, so-called "secondary necrosis" (17). After incubation, the neurons were washed twice with PBS and incubated with the two dyes for 15 min.…”

Section: Methodsmentioning

confidence: 99%

Bilirubin Induces Apoptosis and Necrosis in Human NT2-N Neurons

et al. 2005

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Studies on primary cultures of newborn rodent neurons have suggested that neuronal death induced by unconjugated bilirubin (UCB) is mainly apoptotic in nature. We exposed a human teratocarcinoma-derived cell line, NT2-N neurons, to different concentrations of UCB and albumin at a 1.5 molar ratio and used multiple, independent measures of cell damage to evaluate neuronal injury after 6, 24, and 48 h. Low doses of UCB (0.66, 2, and 5 M) induced a moderate loss of 3-4[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide (MTT) cleavage accompanied by delayed morphologic changes consistent with apoptosis (2 and 5 M). Moderate concentrations of UCB (10 and 25 M) resulted in early (6 h) necrosis in a subset of neurons, while remaining neurons underwent progressive impairment of MTT cleavage and increasing lactate dehydrogenase (LDH) release accompanied by predominantly delayed apoptosis. High concentrations of UCB (100 M) induced severe impairment of MTT cleavage, extensive LDH release, and morphologic changes consistent with necrosis within 6 h. Used as a positive control for apoptosis, 2 M STS induced progressive impairment of MTT cleavage and morphologic changes consistent with apoptosis over the entire observation period. DNA electrophoresis at 48 h was compatible with apoptosis both after treatment with STS and UCB concentrations Յ25, but not at 100 M. Cleavage of poly (ADP-ribose) polymerase (PARP) was only seen in neurons treated with low UCB concentrations and STS. We conclude that UCB induces early necrosis at high and moderate concentrations and predominantly delayed apoptosis at low and moderate concentrations in cultured human NT2-N neurons. Bilirubin-induced encephalopathy in the newborn has been described for over a century. The term is mainly used to describe a picture of reversible lethargy and alterations in cerebral evoked potentials thought to be benign (1). The term kernicterus has been used to describe more severe clinical manifestations like seizures, opisthotonos, and hyperthermia in the acutely ill newborn, followed by neurologic sequelae in survivors or death (1). The question of whether these manifestation share a common graded mechanism or reflect different entities is not settled (2).Previously, neuronal death has been thought of as the result of either necrosis or apoptosis (3). However, it now seems that apoptosis and necrosis represent extreme ends of a spectrum of possible biochemical and morphologic deaths, so that a more dynamic boundary between apoptosis and necrosis has been suggested (3). Several studies have shown that it is often the magnitude of the initial insult, rather than the specific type of the stimulus, that determines whether the cell undergoes either type of cell death (3,4). Recently, several studies have reported that UCB primarily induces apoptosis both in primary cultures of fetal cortical and cerebellar rodent neurons (5,6), in cultures

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“…This figure does not seem to reflect a real cell number of (28) and apoptotic cell death of motor neurons in vitro by free radical treatment (17). Our in vitro study shows that addition of the CM from ASC culture and cytokines/growth factors produced from ASCs effectively block apoptotic cell death of spinal cord cells caused by H 2 O 2 (Fig.…”

Section: Discussionmentioning

confidence: 75%

Transplantation of Human Adipose Tissue-Derived Stem Cells Delays Clinical Onset and Prolongs Life Span in ALS Mouse Model

Kim

Lee

et al. 2014

Cell Transplant

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects motor neurons in the cortex, brain stem, and spinal cord. The precise pathogenic mechanism remains unknown, and there is currently no effective therapy. We evaluated the therapeutic effects of human adipose tissue-derived stem cells (ASCs) in an animal model of ALS. Human abdominal subcutaneous fat tissues were obtained by simple liposuction from donors, and ASCs were isolated from the fat stromal vascular fraction. ASCs were found to differentiate into adipocytes, chondrocytes, osteocytes, and neurons. SOD1G93A ALS mice were divided into three groups: sham, intravenous (IV), and intracerebroventricular (ICV) groups. Human ASCs were transplanted in the ALS mice at 70 postnatal days before the appearance of clinical symptoms. Behavior of transplanted animals was assessed by rotarod test, paw grip endurance (PaGE), and reflex index. Mice in every group were sacrificed after 4 weeks posttransplantation. Transplanted ASCs were identified in the lumbar spinal cords with an antihuman mitochondria antibody and cell type-specific markers for neurons or astrocytes. Delayed onset of clinical symptoms (26 days) and extended survival of animals (24 days) were observed in ALS mice transplanted with ASCs via ICV route. ASCs were found to secrete high levels of neurotrophic factors such as NGF, BDNF, IGF-1, and VEGF. Reduction of apoptotic cell death by these factors was confirmed in cultured CNS cells and in the ALS spinal cord. These results indicate that transplantation of ASCs in ALS mice provides neuroprotective effects by production of cytokines/growth factors, delays disease progression, and prolongs the life span of ALS mice.

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Oxidant treatment causes a dose-dependent phenotype of apoptosis in cultured motoneurons

Cited by 39 publications

References 24 publications

Ang II–Stimulated Superoxide Production Is Mediated via Phospholipase D in Human Vascular Smooth Muscle Cells

Ang II–Stimulated Superoxide Production Is Mediated via Phospholipase D in Human Vascular Smooth Muscle Cells

Bilirubin Induces Apoptosis and Necrosis in Human NT2-N Neurons

Transplantation of Human Adipose Tissue-Derived Stem Cells Delays Clinical Onset and Prolongs Life Span in ALS Mouse Model

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