Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Gene knockout of the KCNJ11-encoded Kir6.2 ATP-sensitive K(+) (K(ATP)) channel implicates this stress-response element in the safeguard of cardiac homeostasis under imposed demand. K(ATP) channels are abundant in ventricular sarcolemma, where subunit expression appears to vary between the sexes. A limitation, however, in establishing the full significance of K(ATP) channels in the intact organism has been the inability to monitor in vivo the contribution of the channel to intracellular calcium handling and the superimposed effect of sex that ultimately defines heart function. Here, in vivo manganese-enhanced cardiac magnetic resonance imaging revealed, under dobutamine stress, a significantly greater accumulation of calcium in both male and female K(ATP) channel knockout (Kir6.2-KO) mice compared with sex- and age-matched wild-type (WT) counterparts, with greatest calcium load in Kir6.2-KO females. This translated, poststress, into a sustained contracture manifested by reduced end-diastolic volumes in K(ATP) channel-deficient mice. In response to ischemia-induced stunning, male and female Kir6.2-KO hearts demonstrated accelerated time to contracture and increased peak contracture compared with WT. The outcome on reperfusion, in both male and female Kir6.2-KO hearts, was a transient reduction in systolic performance, measured as rate-pressure product compared with WT, with protracted increase in left ventricular end-diastolic pressure, exaggerated in female knockout hearts, despite comparable leakage of creatine kinase across groups. Kir6.2-KO hearts were rescued from diastolic dysfunction by agents that target alternative pathways of calcium handling. Thus K(ATP) channel deficit confers a greater susceptibility to calcium overload in vivo, accentuated in female hearts, impairing contractile recovery under various conditions of high metabolic demand.
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PMID:KATP channel knockout worsens myocardial calcium stress load in vivo and impairs recovery in stunned heart. 1725 43

ATP-sensitive potassium channels (K(ATP)) couple cell metabolism to electrical activity by regulating potassium movement across the membrane. These channels are octameric complex with two kind of subunits: four regulatory sulfonylurea receptor (SUR) embracing four poreforming inwardly rectifying potassium channel (Kir). Several isoforms exist for each type of subunits: SUR1 is found in the pancreatic beta-cell and neurons, whereas SUR2A is in heart cells and SUR2B in smooth muscle; Kir6.2 is in the majority of tissues as pancreatic beta-cells, brain, heart and skeletal muscle, and Kir6.1 can be found in smooth vascular muscle and astrocytes. The K(ATP) channels play multiple physiological roles in the glucose metabolism regulation, especially in beta-cells where it regulates insulin secretion, in response to an increase in ATP concentration. They also seem to be critical metabolic sensors in protection against metabolic stress as hypo or hyperglycemia, hypoxia, ischemia. Persistent hyperinsulinemic hypoglycaemia (HI) of infancy is a heterogeneous disorder which may be divided into two histopathological forms (diffuse and focal lesions). Different inactivating mutations have been implicated in both forms: the permanent inactivation of the K(ATP) channels provokes inappropriate insulin secretion, despite low ATP. Diazoxide, used efficiently in certain cases of HI, opens the K(ATP) channels and therefore overpass the mutation effect on the insulin secretion. Conversely, several studies reported sequencing of KCNJ11, coding for Kir6.2, in patients with permanent neonatal diabetes mellitus and found different mutations in 30 to 50% of the cases. More than 28 heterozygous activating mutations have now been identified, the most frequent mutation being in the aminoacid R201. These mutations result in reduced ATP-sensitivity of the K(ATP) channels compared with the wild-types and the level of channel block is responsible for different clinical features: the "mild" form confers isolated permanent neonatal diabetes whereas the severe form combines diabetes and neurological symptoms such as epilepsy, deve-lopmental delay, muscle weakness and mild dimorphic features. Sulfonylureas close K(ATP) channels by binding with high affinity to SUR suggesting they could replace insulin in these patients. Subsequently, more than 50 patients have been reported as successfully and safely switched from subcutaneous insulin injections to oral sulfonylurea therapy, with an improvement in their glycated hemoglobin. We therefore designed a protocol to transfer and evaluate children who have insulin treated neonatal diabetes due to KCNJ11 mutation, from insulin to sulfonylurea. The transfer from insulin injections to oral glibenclamide therapy seems highly effective for most patients and safe. This shows how the molecular understan-ding of some monogenic form of diabetes may lead to an unexpected change of the treatment in children. This is a spectacular example by which a pharmacogenomic approach improves the quality of life of our young diabetic patients in a tremendous way.
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PMID:Diabetes and hypoglycaemia in young children and mutations in the Kir6.2 subunit of the potassium channel: therapeutic consequences. 1729 10

To investigate the mechanisms regulating excitation-metabolic coupling in rabbit epicardial, midmyocardial, and endocardial ventricular myocytes we extended the LabHEART model (Puglisi JL and Bers DM. Am J Physiol Cell Physiol 281: C2049-C2060, 2001). We incorporated equations for Ca(2+) and Mg(2+) buffering by ATP and ADP, equations for nucleotide regulation of ATP-sensitive K(+) channel and L-type Ca(2+) channel, Na(+)-K(+)-ATPase, and sarcolemmal and sarcoplasmic Ca(2+)-ATPases, and equations describing the basic pathways (creatine and adenylate kinase reactions) known to communicate the flux changes generated by intracellular ATPases. Under normal conditions and during 20 min of ischemia, the three regions were characterized by different I(Na), I(to), I(Kr), I(Ks), and I(Kp) channel properties. The results indicate that the ATP-sensitive K(+) channel is activated by the smallest reduction in ATP in epicardial cells and largest in endocardial cells when cytosolic ADP, AMP, PCr, Cr, P(i), total Mg(2+), Na(+), K(+), Ca(2+), and pH diastolic levels are normal. The model predicts that only K(ATP) ionophore (Kir6.2 subunit) and not the regulatory subunit (SUR2A) might differ from endocardium to epicardium. The analysis suggests that during ischemia, the inhomogeneous accumulation of the metabolites in the tissue sublayers may alter in a very irregular manner the K(ATP) channel opening through metabolic interactions with the endogenous PI cascade (PIP(2), PIP) that in turn may cause differential action potential shortening among the ventricular myocyte subtypes. The model predictions are in qualitative agreement with experimental data measured under normal and ischemic conditions in rabbit ventricular myocytes.
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PMID:Modeling transmural heterogeneity of K(ATP) current in rabbit ventricular myocytes. 1732 4

In clinic, the patients with acute myocardial infarction (AMI) are at high risk to develop ischemia-induced ventricular arrhythmias leading to sudden cardiac death (SCD). Some studies suggest that individual susceptibility to ischemia-induced arrhythmia may be related to the genes encoding ion channels. One of them is the cardiac ATP-sensitive potassium channel (K(ATP)), which is an octamer composed of four pore-forming inwardly rectifying potassium-channel subunits (Kir6.2) and four regulatory sulfonylurea-receptor subunits (SUR2A). They play important roles in the physiology and pathophysiology of cardiovascular system by coupling the metabolic state of the cells to cellular electrical activity. So far, some mutations and polymorphisms of Kir6.2/KCNJ11 gene showed significant correlation with type 2 diabetes. But it was not sure whether it was associated with acute myocardial diseases. Hence a complete mutational analysis of Kir6.2/KCNJ11 gene was performed in a pedigree of sudden cardiac death. The complete coding region and the intron-exon boundaries of KCNJ11 were amplified from genomic DNA using polymerase chain reaction (PCR). Direct sequencing was done to identify any mutations and then further confirmed by restriction site polymorphism (RSP) approach. No mutation was detected in the samples analyzed, a common polymorphism K23E (A>G) was noticed in this pedigree and the proband showed a homozygote genotype (G/G). The result suggests that the Kir6.2/KCNJ11 gene is not related to sudden cardiac death in this family.
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PMID:Study of Kir6.2/KCNJ11 gene in a sudden cardiac death pedigree. 1743 20

Hypoxic gasping emerges under severe hypoxia/ischemia in various species, exerting a life-protective role by assuring minimum ventilation even in loss of consciousness. However, the molecular basis of its generation and maintenance is not well understood. Here we found that mice lacking Kir6.2- but not Kir6.1-containing ATP-sensitive potassium (K(ATP)) channels [knockout (KO) mice] exhibited few gaSPS when subjected to abrupt ischemia by decapitation, whereas wild-type mice all exhibited more than 10 gaSPS. Under anesthesia, wild-type mice initially responded to severe hypoxic insult with augmented breathing (tachypnea) accompanied by sighs and subsequent depression of respiratory frequency. Gasping then emerged and persisted stably (persistent gasping); if the hypoxia continued, several gaSPS with distinct patterns appeared (terminal gasping) before cessation of breathing. KO mice showed similar hypoxic responses but both depression and the two types of gasping were of much shorter duration than in wild-type mice. Moreover, in the unanesthetized condition, the onset of terminal gasping in KO mice, which was always earlier than in wild-type mice, was unaltered by decreasing O(2) concentrations within the severe range (4.5-7.0%), whereas onset in wild-type mice became earlier in response to lowered O(2) concentrations. Thus, the mechanism responsible for regulating the hypoxic response in accordance with the severity of the hypoxia was dysfunctional in these KO mice, suggesting that Kir6.2-containing K(ATP) channels are critically involved in the maintenance rather than the generation of hypoxic gasping and depression of respiratory frequency.
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PMID:Disruption of Kir6.2-containing ATP-sensitive potassium channels impairs maintenance of hypoxic gasping in mice. 1744 33

Adenosine triphosphate-sensitive potassium (K(ATP)) channels are thought to mediate the stress response by sensing intracellular ATP concentration. Cardiomyocyte K(ATP) channels are composed of the pore-forming Kir6.2 subunit and the regulatory sulfonylurea receptor 2 (SUR2). We studied the response to acute isoproterenol in SUR2 null mice as a model of acute adrenergic stress and found that the episodic coronary vasospasm observed at baseline in SUR2 null mice was alleviated. Similar results were observed following administration of a nitric oxide donor consistent with a vasodilatory role. Langendorff-perfused hearts were subjected to global ischemia, and hearts from SUR2 null mice exhibited significantly reduced infarct size (54+/-4 versus 30+/-3%) and improved cardiac function compared to control mice. SUR2 null mice have hypertension and develop cardiac hypertrophy. However, despite longstanding hypertension, fibrosis was absent in SUR2 null mice. SUR2 null mice were administered nifedipine to block baseline coronary vasospasm, and hearts from nifedipine-treated SUR2 null mice exhibited increased infarct size compared to untreated SUR2 null mice (42+/-3% versus 54+/-3%). We conclude that conventional sarcolemmal cardiomyocyte K(ATP) channels containing full-length SUR2 are not required for mediating the response to acute cardiovascular stress.
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PMID:Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress. 1776 61

We examined the cardioprotective profile of the new A(3) adenosine receptor (AR) agonist CP-532,903 [N(6)-(2,5-dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] in an in vivo mouse model of infarction and an isolated heart model of global ischemia/reperfusion injury. In radioligand binding and cAMP accumulation assays using human embryonic kidney 293 cells expressing recombinant mouse ARs, CP-532,903 was found to bind with high affinity to mouse A(3)ARs (K(i) = 9.0 +/- 2.5 nM) and with high selectivity versus mouse A(1)AR (100-fold) and A(2A)ARs (1000-fold). In in vivo ischemia/reperfusion experiments, pretreating mice with 30 or 100 microg/kg CP-532,903 reduced infarct size from 59.2 +/- 2.1% of the risk region in vehicle-treated mice to 42.5 +/- 2.3 and 39.0 +/- 2.9%, respectively. Likewise, treating isolated mouse hearts with CP-532,903 (10, 30, or 100 nM) concentration dependently improved recovery of contractile function after 20 min of global ischemia and 45 min of reperfusion, including developed pressure and maximal rate of contraction/relaxation. In both models of ischemia/reperfusion injury, CP-532,903 provided no benefit in studies using mice with genetic disruption of the A(3)AR gene, A(3) knockout (KO) mice. In isolated heart studies, protection provided by CP-532,903 and ischemic preconditioning induced by three brief ischemia/reperfusion cycles were lost in Kir6.2 KO mice lacking expression of the pore-forming subunit of the sarcolemmal ATP-sensitive potassium (K(ATP)) channel. Whole-cell patch-clamp recordings provided evidence that the A(3)AR is functionally coupled to the sarcolemmal K(ATP) channel in murine cardiomyocytes. We conclude that CP-532,903 is a highly selective agonist of the mouse A(3)AR that protects against ischemia/reperfusion injury by activating sarcolemmal K(ATP) channels.
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PMID:The A3 adenosine receptor agonist CP-532,903 [N6-(2,5-dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP-sensitive potassium channel. 1790 66

Neuroprotection against cerebral ischemia conferred by ischemic preconditioning (IPC) requires translocation of epsilon protein kinase C (epsilonPKC). A major goal in our laboratory is to define the cellular targets by which epsilonPKC confers protection. We tested the hypothesis that epsilonPKC targets the mitochondrial K(+)(ATP) channel (mtK(+)(ATP)) after IPC. Our results demonstrated a rapid translocation of epsilonPKC to rat hippocampal mitochondria after IPC. Because in other tissues epsilonPKC targets mtK(+)(ATP) channels, but its presence in brain mitochondria is controversial, we determined the presence of the K(+)(ATP) channel-specific subunits (Kir6.1 and Kir6.2) in mitochondria isolated from rat hippocampus. Next, we determined whether mtK(+)(ATP) channels play a role in the IPC induction. In hippocampal organotypic slice cultures, IPC and lethal ischemia were induced by oxygen-glucose deprivation. Subsequent cell death in the CA1 region was quantified using propidium iodide staining. Treatment with the K(+)(ATP) channel openers diazoxide or pinacidil 48 h prior to lethal ischemia protected hippocampal CA1 neurons, mimicking the induction of neuroprotection conferred by either IPC or epsilonPKC agonist-induced preconditioning. Blockade of mtK(+)(ATP) channels using 5-hydroxydecanoic acid abolished the neuroprotection due to either IPC or epsilonPKC preconditioning. Both ischemic and epsilonPKC agonist-mediated preconditioning resulted in phosphorylation of the mtK(+)(ATP) channel subunit Kir6.2. After IPC, selective inhibition of epsilonPKC activation prevented Kir6.2 phosphorylation, consistent with Kir6.2 as a phosphorylation target of epsilonPKC or its downstream effectors. Our results support the hypothesis that the brain mtK(+)(ATP) channel is an important target of IPC and the signal transduction pathways initiated by epsilonPKC.
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PMID:epsilonPKC phosphorylates the mitochondrial K(+) (ATP) channel during induction of ischemic preconditioning in the rat hippocampus. 1798 55

Mice with genetic inhibition (AC3-I) of the multifunctional Ca(2+)/calmodulin dependent protein kinase II (CaMKII) have improved cardiomyocyte survival after ischemia. Some K(+) currents are up-regulated in AC3-I hearts, but it is unknown if CaMKII inhibition increases the ATP sensitive K(+) current (I(KATP)) that underlies ischemic preconditioning (IP) and confers resistance to ischemia. We hypothesized increased I(KATP) was part of the mechanism for improved ventricular myocyte survival during ischemia in AC3-I mice. AC3-I hearts were protected against global ischemia due to enhanced IP compared to wild type (WT) and transgenic control (AC3-C) hearts. IKATP was significantly increased, while the negative regulatory dose-dependence of ATP was unchanged in AC3-I compared to WT and AC3-C ventricular myocytes, suggesting that CaMKII inhibition increased the number of functional I(KATP) channels available for IP. We measured increased sarcolemmal Kir6.2, a pore-forming I(KATP) subunit, but not a change in total Kir6.2 in cell lysates or single channel I(KATP) opening probability from AC3-I compared to WT and AC3-C ventricles, showing CaMKII inhibition increased sarcolemmal I(KATP) channel expression. There were no differences in mRNA for genes encoding I(KATP) channel subunits in AC3-I, WT and AC3-C ventricles. The I(KATP) opener pinacidil (100 microM) reduced MI area in WT to match AC3-I hearts, while the I(KATP) antagonist HMR1098 (30 microM) increased MI area to an equivalent level in all groups, indicating that increased I(KATP) and augmented IP are important for reduced ischemic cell death in AC3-I hearts. Our study results show CaMKII inhibition enhances beneficial effects of IP by increasing I(KATP).
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PMID:Calmodulin kinase II inhibition enhances ischemic preconditioning by augmenting ATP-sensitive K+ current. 1869 39

The activation of cardiac cell membrane ATP-sensitive potassium channels during myocardial ischemia promotes potassium efflux, reductions in action potential duration, and heterogeneities in repolarization, thereby creating a substrate for re-entrant arrhythmias. Drugs that block this channel should be particularly effective anti-arrhythmic agents. Indeed, non-selective ATP-sensitive potassium channel antagonists, (e.g., glibenclamide) can prevent arrhythmias associated with myocardial ischemia. However, these non-selective antagonists have important non-cardiac actions that promote insulin release and hypoglycemia (pancreatic beta-cells), reduce coronary blood flow (vascular smooth muscle cells), prevent ischemia preconditioning (cardiac mitochondrial channels) and depress cardiac contractile function. The ATP-sensitive potassium channel consists of a pore forming inward rectifying potassium channel (Kir6.1 or Kir6.2) and a regulatory subunit (sulfonylurea receptors, SUR1, SUR2A &SUR2B). The Kir6.2/SUR2A combination appears to be preferentially expressed on cardiac cell membranes. As such, it should be possible to develop agents selective for cardiac sarcolemmal ATP-sensitive potassium channels. The novel compounds HMR 1883 (or its sodium salt HMR 1098) or HMR 1402 have been shown to block selectively the cardiac sarcolemmal ATP-sensitive potassium channels. These drugs attenuated ischemically-induced changes in cardiac electrical properties and prevented malignant arrhythmias without the untoward effects of other drugs. Since the ATP-sensitive potassium channel only becomes active as ATP levels fall, these drugs have the added advantage that they would have effects only on ischemic tissue with little or no effect noted on normal tissue. Thus, selective antagonists of the cardiac cell surface ATP-sensitive potassium channel may represent a new class of ischemia selective anti-arrhythmic medications.
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PMID:The cardiac sarcolemmal ATP-sensitive potassium channel as a novel target for anti-arrhythmic therapy. 1870 91


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