Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obstructive sleep apnea (OSA) is associated with cardiovascular diseases such as hypertension through mechanisms involving intermittent hypoxia (IH). However, it is not yet clear whether IH directly affects the heart. In a mouse model of OSA, we found that IH causes time-dependent alterations of the susceptibility of the heart to oxidative stress. Acute IH can exert preconditioning-like cardioprotection, in part, through the transcriptional activation of genes such as bcl-x(L) and gata4. We cloned the mouse gata4 promoter and identified an IH-responsive region. The exposure of mice to prolonged IH results in the increased susceptibility of the heart to ischemia-reperfusion injury by increasing the oxidative stress status. This might resemble conditions of OSA patients. In our mouse model, further exposure to prolonged IH allowed reversal of the enhancement of myocardial damage. Understanding the complex effects of IH on the heart should help ultimately to develop therapeutic strategies against OSA-induced complications.
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PMID:Effects of intermittent hypoxia on the heart. 1751 87

Numerous studies have demonstrated evidence of DNA nick end-labeling and DNA laddering following cerebral ischemia. To determine whether genes directly implicated in apoptosis were induced by ischemia, the expression of bcl-2, bcl-x and ICE mRNAs were examined using oligonucleotide probes. Northern blots demonstrated induction of bcl-2 mRNA and bcl-x mRNAs in hippocampus 24 and 72 h following 5 min of global ischemia. In situ hybridization demonstrated induction of bcl-2 and bcl-x mRNAs in CAl pyramidal neurons of hippocampus at 24 h following ischemia which decreased by 72 h. ICE-like mRNA was induced in non-neuronal cells in the CAl region at 72 h following global ischemia. The data show that genes implicated in either protecting against or promoting programmed cell death in other systems are induced following cerebral ischemia. It is hypochesized that CAl neuronal cell death could be accounted for by the failure of the ischemic cells to make protective proteins that protect the cells from an ischemic induced apoptotic-like cell death.
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PMID:Apoptosis associated genes are induced in gerbil hippocampus following global ischemia. 2155 11

The bcl-x gene appears to play a critical role in regulating apoptosis in the developing and mature CNS and following CNS injury. Two isoforms of Bcl-x are produced as a result of alternative pre-mRNA splicing: Bcl-x(L) (the long form) is anti-apoptotic, while Bcl-x(S) (short form) is pro-apoptotic. Despite the antagonistic activities of these two isoforms, little is known about how regulation of alternative splicing of bcl-x may mediate neural cell apoptosis. Here, we report that apoptotic stimuli (staurosporine or C2-ceramide) reciprocally altered Bcl-x splicing in neural cells, decreasing Bcl-x(L) while increasing Bcl-x(S). Specific knockdown of Bcl-x(S) attenuated apoptosis. To further define regulatory elements that influenced Bcl-x splicing, a Bcl-x minigene was constructed. Deletional analysis revealed several consensus sequences within intron 2 that altered splicing. We found that the splicing factor, CUG-binding-protein-1 (CUGBP1), bound to a consensus sequence close to the Bcl-x(L) 5' splice site, altering the Bcl-x(L)/Bcl-x(S) ratio and influencing cell death. In vivo, neonatal hypoxia-ischemia reciprocally altered Bcl-x pre-mRNA splicing, similar to the in vitro studies. Manipulation of the splice isoforms using viral gene transfer of Bcl-x(S) shRNA into the hippocampus of rats before neonatal hypoxia-ischemia decreased vulnerability to injury. Moreover, alterations in nuclear CUGBP1 preceded Bcl-x splicing changes. These results suggest that alternative pre-mRNA splicing may be an important regulatory mechanism for cell death after acute neurological injury and may potentially provide novel targets for intervention.
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PMID:Bcl-x pre-mRNA splicing regulates brain injury after neonatal hypoxia-ischemia. 2301 48


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