The role of calcium in hypoxia-induced signal transduction and gene expression
Department of Genome Science, Genome Research Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA. Cell Calcium
(Impact Factor: 3.51).
09/2004; 36(3-4):331-40. DOI: 10.1016/j.ceca.2004.02.006
Mammalian cells require a constant supply of oxygen in order to maintain adequate energy production, which is essential for maintaining normal function and for ensuring cell survival. Sustained hypoxia can result in cell death. Sophisticated mechanisms have therefore evolved which allow cells to respond and adapt to hypoxia. Specialized oxygen-sensing cells have the ability to detect changes in oxygen tension and transduce this signal into organ system functions that enhance the delivery of oxygen to tissue in a wide variety of different organisms. An increase in intracellular calcium levels is a primary response of many cell types to hypoxia/ischemia. The response to hypoxia is complex and involves the regulation of multiple signaling pathways and coordinated expression of perhaps hundreds of genes. This review discusses the role of calcium in hypoxia-induced regulation of signal transduction pathways and gene expression. An understanding of the molecular events initiated by changes in intracellular calcium will lead to the development of therapeutic approaches toward the treatment of hypoxic/ischemic diseases and tumors.
Available from: Hae-Hyeog Lee
- "However, several randomized trials have reported the effective use of various methods to reduce the rate or severity of preeclampsia (Sibai et al., 2005), including Ca 2+ supplementation (Hofmeyr et al., 2007; Belizan et al., 1991). Although two clinical trials evaluating the ability of dietary Ca 2+ supplementation to prevent preeclampsia produced disparate results (Belizan et al., 1991; Levine et al., 1997), increased intracellular Ca 2+ levels have been implicated in the development of cell injury and hypoxic stress (Seta et al., 2004). Furthermore, Ca 2+ entry blockers have been reported to protect against cellular necrosis caused by experimental ischemia in the liver, kidney and other tissues (Peck and Lefer, 1981; Lee and Lum, 1986). "
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ABSTRACT: Preeclampsia is a pregnancy-specific disease characterized by hypertension, proteinuria, and oxidative stress in the placenta. During the last trimester of gestation, calcium (Ca(2+)) transport from mother to fetus increases dramatically in response to the increased demand for Ca(2+) caused by bone mineralization in the fetus. Ca(2+) supplementation can significantly reduce the incidence and severity of preeclampsia or delay its onset. Ca(2+) transport channels (CTCs) include transient receptor potential vanilloid 6 (TRPV6), plasma membrane Ca(2+) ATPase (PMCA1), and Na(+)/Ca(2+) exchangers (NCKX3 or NCX1). We hypothesized that trans-placental Ca(2+) exchange in preeclamptic trophoblasts may be compensated for successful fetal bone mineralization. The roles of cell membrane channels (TRPV6, PMCA1, NCKX3 and NCX1) were examined in placental primary cells and in normotensive and preeclamptic placentas. The biomarker gene for preeclampsia, soluble fms-like tyrosine kinase-1 (sFLT1) or marker for oxygen-sensitive gene, hypoxia-sensitive inducible factor 1α (HIF-1α), were up-regulated in the preeclamptic placentas and hypoxic cells. The detection of sFLT1 and HIF-1α genes demonstrated that our experimental conditions were suitable to verify a preeclamptic condition. In women experiencing preterm labor, CTC expressions was found to be increased in the fetal and maternal regions of the preeclamptic placenta compared to the observed in normotensive placenta. During term labor, TRPV6 and PMCA1 were highly expressed in the fetal and maternal sections of preeclamptic placenta, while the expression of NCKX3 and NCX1 was reduced. In addition, the expression of CTCs was altered in hypoxia-stressed placental cells. Taken together, our findings demonstrated that the expression of CTCs was regulated by hypoxia stress in placenta tissues and cells, suggesting that our experimental in vitro hypoxic conditions were similar to those of preeclampsia. Furthermore, impaired Ca(2+) metabolism found in preeclamptic syncytiotrophoblasts was resulted from hypoxic stress, which may induce expression of Ca(2+) transport proteins in the placenta to maintain the balance between maternal and fetal Ca(2+) demand during pregnancy.
Available from: Jiang-Ping Xu
- "Massive Ca 2+ influx may involve several mechanisms, such as activation of nitric oxide synthase, calcium-sensitive proteases, and mitochondrial damage, which consequently contribute to the breakdown of the cell membrane, cytoskeleton , and genomic DNA (Lau and Tymianski 2010). An increasing body of evidence indicates that a dramatic decrease in mitochondrial Ca 2+ retention may lead to cell death associated with neurodegenerative diseases, such as cerebral ischemia (ArundineSeta et al. 2004). This result is supported by the anti-ischemic effects of levosimendan via the PI3K–Akt pathway in improving cardiac contractile function after ischemia and reperfusion (Honisch et al. 2010). "
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ABSTRACT: Objective: To investigate the effect of piperphentonamine (PPTA) on global cerebral ischemia/reperfusion (I/R) injury in rats. Methods: Global I/R injury was induced by four-vessel occlusion in rats. Then the rats were randomly divided into control, I/R, and PPTA (2.5, 5 and 10 mg·kg -1) groups. Morris water maze was used to evaluate the learning and memory abilities. The histological changes in the hippocampus were observed after Nissl staining. LDH activity and the expression of bax/bcl-2, caspase-3 and iNOS mRNA were measured by colorimetric assay kit and real-time PCR. Results: PPTA (5 and 10 mg·kg -1) significantly shortened escape latency in the Morris water maze test, and protected neurons from injury. The LDH activity and the expression of bax/bcl-2, caspase-3 and iNOS were reduced compared with I/R group. Conclusion: PPTA can reduce neuronal damage in the hippocampus, and enhance the ability of learning and memory after global I/R injury in rats.
Available from: ncbi.nlm.nih.gov
- "derlying molecular mechanisms have not been fully demonstrated, it has been reported that nonlethal levels of hypoxia can sometimes lead to the upregulation of cell survival genes and signaling pathways (Seta et al., 2004). Cheng and colleagues (Cheng et al., 2007) reported that hypoxia reduced PQ-induced cellular damage in human corneal endothelial cells. "
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ABSTRACT: Paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride; PQ), an effective and widely used herbicide, was commercially introduced in 1962. It is reduced by the electron donor NADPH, and then reduced PQ transfers the electrons to molecular oxygen, resulting in the production of reactive oxygen species (ROS), which are related to cellular toxicity. However, the influence of continuous hypoxia on PQ-induced ROS production has not fully been investigated. We evaluated in vitro the protective effect of continuous hypoxia on PQ-induced cytotoxicity in the human carcinogenic alveolar basal epithelial cell line (A549 cells) by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and live and dead assay, and by measuring lactate dehydrogenase (LDH) release. To elucidate the mechanism underlying this effect, we monitored the immunofluorescence of intracellular ROS and measured malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Continuous hypoxia protected the A549 cells from PQ-induced cytotoxicity. Continuous hypoxia for a period of 24 h significantly reduced intracellular ROS, decreased MDA concentration in the supernatant, and normalized SOD and GPx activities. Continuous hypoxia attenuated PQ-induced cell toxicity in A549 cells. This protective effect might be attributable to the suppression of PQ-induced ROS generation.
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