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)

Sudden infant death syndrome (SIDS) is characterized by a lack of any known morphological or functional organ changes that could explain the lethal process. In the present study we investigated the hypothesis of an association between hypoxic/ischemic injury and SIDS deaths. In a previous study, we could demonstrate by quantitative immunohistochemistry a distinct drop in microtubule-associated protein (MAP2) reactivity in neurons of adult, human brains secondary to acute hypoxic-ischemic injuries. Here we applied the same method on sections of the frontal cortex and hippocampus of 41 brains of infants younger than 1 year of age. For each brain area 100 selected neurons were evaluated for their MAP2 reactivity in the different layers of the frontal cortex and in the different segments of the hippocampus. Three groups were compared: (1) SIDS victims (n = 17), (2) infants with hypoxia/ischemia (control group one; n = 14), (3) infants without hypoxic/ischemic injury (control group two; n = 10). The SIDS group and hypoxic/ischemic group exhibited a general reduction in the number of MAP2 reactive neurons in comparison with the non-hypoxic/ischemic injury group. The SIDS group also had a significantly lower (P < 0.05) number of reactive neurons in the CA2 and CA3 areas of the hippocampus than did control group two. No difference was detected between the SIDS group and control group one. The SIDS brains were thus found to display hypoxic/ischemic features without however providing evidence as to the cause of the oxygen reduction.
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PMID:Hypoxic-ischemic changes in SIDS brains as demonstrated by a reduction in MAP2-reactive neurons. 1920 8

Eupnea is normal breathing. If eupnea fails, as in severe hypoxia or ischemia, gasping is recruited. Gasping can serve as a powerful mechanism for autoresuscitation. A failure of autoresuscitation has been proposed as a basis of the sudden infant death syndrome. In an in vitro preparation, endogenous serotonin is reported to be essential for expression of gasping. Using an in situ preparation of the Pet-1 knockout mouse, we evaluated such a critical role for serotonin. In this mouse, the number of serotonergic neurons is reduced by 85-90% compared with animals without this homozygous genetic defect. Despite this reduction in the number of serotonergic neurons, phrenic discharge in eupnea and gasping of Pet-1 knockout mice was not different from that of wild-type mice. Indeed, gasping continued unabated, even after administration of methysergide, a blocker of many types of receptors for serotonin, to Pet-1 knockout mice. We conclude that serotonin is not critical for expression of gasping. The proposal for such a critical role, on the basis of observations in the in vitro slice preparation, may reflect the minimal functional neuronal tissue and neurotransmitters in this preparation, such that the role of any remaining neurotransmitters is magnified. Also, rhythmic activity of the in vitro slice preparation has been characterized as eupnea or gasping solely on the basis of activity of the hypoglossal nerve or massed neuronal activities of the ventrolateral medulla. The accuracy of this method of classification has not been established.
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PMID:Genesis of gasping is independent of levels of serotonin in the Pet-1 knockout mouse. 1921 35

The SCN5A-encoded cardiac sodium channel underlies excitability in the heart, and dysfunction of sodium current (I(Na)) can cause fatal ventricular arrhythmia in maladies such as long QT syndrome, Brugada syndrome (BrS), and sudden infant death syndrome (SIDS). The gene GPD1L encodes the glycerol phosphate dehydrogenase 1-like protein with homology to glycerol phosphate dehydrogenase (GPD1), but the function for this enzyme is unknown. Mutations in GPD1L have been associated with BrS and SIDS and decrease I(Na) through an unknown mechanism. Using a heterologous expression system, we show that GPD1L associated with SCN5A and that the BrS- and SIDS-related mutations in GPD1L caused a loss of enzymatic function resulting in glycerol-3-phosphate PKC-dependent phosphorylation of SCN5A at serine 1503 (S1503) through a GPD1L-dependent pathway. The direct phosphorylation of S1503 markedly decreased I(Na). These results show a function for GPD1L in cell physiology and a mechanism linking mutations in GPD1L to sudden cardiac arrest. Because the enzymatic step catalyzed by GPD1L depends upon nicotinamide adenine dinucleotide, this GPD1L pathway links the metabolic state of the cell to I(Na) and excitability and may be important more generally in cardiac ischemia and heart failure.
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PMID:GPD1L links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel SCN5A. 1966 41

The sarcolemmal adenosine triphosphate (ATP)-sensitive K(+) (sarcKATP) channel in the heart is a hetero-octamer comprising the pore-forming subunit Kir6.2 and the regulatory subunit sulfonylurea receptor SUR2A. By functional analysis of genetically engineered mice lacking sarcKATP channels, the pathophysiological roles of the K(+) channel in the heart have been extensively evaluated. Although mitochondrial KATP (mitoKATP) channel is proposed to be an important effector for the protection of ischemic myocardium and the inhibition of ischemia/reperfusion-induced ventricular arrhythmias, the molecular identity of mitoKATP channel has not been established. Although selective sarcKATP-channel blockers can prevent ischemia/reperfusion-induced ventricular arrhythmias by inhibiting the action potential shortening in the acute phase, the drugs may aggravate the ischemic damages due to intracellular Ca(2+) overload. The sarcKATP channel is also mandatory for optimal adaptation to hemodynamic stress such as sympathetic activation. Dysfunction of mutated sarcKATP channels in atrial cells may lead to electrical instability and atrial fibrillation. Recently, it has been proposed that the gain-of-function mutation of cardiac Kir6.1 channel can be a pathogenic substrate for J wave syndromes, a cause of idiopathic ventricular fibrillation as early repolarization syndrome or Brugada syndrome, whereas loss of function of the channel mutations can underlie sudden infant death syndrome. However, precise role of Kir6.1 channels in cardiac cells remains to be defined and further study may be needed to clarify the role of Kir6.1 channel in the heart.
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PMID:Role of ATP-sensitive K+ channels in cardiac arrhythmias. 2436 7

Sodium current in the heart flows principally through the pore protein NaV1.5, which is part of a complex of interacting proteins that serve both to target and localize the complex in the membrane, and to modulate function by such post-translational modifications as phosphorylation and nitrosylation. Multiple mutations in seven different NaV1.5 interacting proteins have been associated with dysfunctional sodium current and inherited cardiac diseases, including long QT syndrome, Brugada syndrome, atrial fibrillation, and cardiomyopathy, as well as sudden infant death syndrome (SIDS). Mutations in as yet unidentified interacting proteins may account for cardiac disease for which a genetic basis has not yet been established. Characterizing the mechanisms by which these mutations cause disease may give insight into etiologies and treatments of more common acquired cardiac disease, such as ischemia and heart failure.
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PMID:Diseases caused by mutations in Nav1.5 interacting proteins. 2539 96


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