Myocardial ischemia induces differential regulation of KATP channel gene expression in rat hearts.

Akao, Masaharu; Otani, Haruhisa; Horie, Minoru; Takano, Makoto; Kuniyasu, Akihiko; Nakayama, Hitoshi; Kouchi, Ichiro; Murakami, Tomoyuki; Sasayama, Shígetake

doi:10.1172/jci119860

Cited by 69 publications

(28 citation statements)

References 34 publications

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“…6,7 It has previously been reported that Kir 6.1 expression is also induced by exposure of the intact heart to I/R. 15 By exposing cultured cardiac cells to 4 hours of simulated ischemia followed by varying periods of reoxygenation, we confirmed that this effect could also be observed in culture with induction of Kir 6.1 being maximal at 16 or 24 hours of reperfusion (Figure 3a). Interestingly, we have previously shown that expression of Ucn itself is induced in cardiac myocytes exposed to ischemia 3 and is responsible for the protective effect of the conditioned medium obtained from ischemic cardiac myocytes.…”

Section: Kir 61 Is Induced By I/r But Not By Ct-1supporting

confidence: 81%

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Lawrence

Giles

1998

Science

725

389

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Background-Urocortin is a novel cardioprotective agent that can protect cardiac myocytes from the damaging effects of ischemia/reperfusion both in culture and in the intact heart and is effective when given at reperfusion. Methods and Results-We have analyzed global changes in gene expression in cardiac myocytes after urocortin treatment using gene chip technology. We report that urocortin specifically induces enhanced expression of the Kir 6.1 cardiac potassium channel subunit. On the basis of this finding, we showed that the cardioprotective effect of urocortin both in isolated cardiac cells and in the intact heart is specifically blocked by both generalized and mitochondrial-specific K ATP channel blockers, whereas the cardioprotective effect of cardiotrophin-1 is unaffected. Conversely, inhibiting the Kir 6.1 channel subunit greatly enhances cardiac cell death after ischemia. Conclusions-This is, to our knowledge, the first report of the altered expression of a K ATP channel subunit induced by a cardioprotective agent and demonstrates that K ATP channel opening is essential for the effect of this novel cardioprotective agent.

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Section: Kir 61 Is Induced By I/r But Not By Ct-1supporting

confidence: 81%

Searching the World Wide Web

Lawrence

Giles

1998

Science

725

389

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“…8,25,53 Interestingly, recent studies unrelated to KATP channels have shown that myocardial infarction, 54 myocardial reperfusion injury, 55 heart failure, 56,57 or myocyte hypertrophy 58 induce an overexpression of FoxO. Other studies unrelated to FoxO have shown increased expression of KIR6.1 following ischemia 16 and exercise. 17 Moreover, recent work suggests that FoxO and KATP channels reduce cardiac ageing and electrical instability in drosophila.…”

Section: E30 Circulation Research February 1 2008mentioning

confidence: 99%

“…14 The brain 2 and skeletal muscle 15 express both KIR6.1 and KIR6.2. The same cardiac tissue may change its subunit composition: subunit Kir6.1 is increasingly expressed in left ventricle following ischemia, 16 exercise, 17 or treatment with K ATP channel agonist. 18 Moreover, differences in subunit composition of cardiac KATP channels arise during development, aging, and between male and female.…”

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confidence: 99%

Forkhead Transcription Factors Coordinate Expression of Myocardial KATP Channel Subunits and Energy Metabolism

Philip-Couderc

Tavares

Roatti

et al. 2008

Circulation Research

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Abstract-Coordinate adaptation of myocyte metabolism and function is fundamental to survival of the stressed heart, but the mechanisms for this coordination remain unclear. Bioinformatics led us to discover that Foxs are key transcription factors involved. We performed experiments on the mouse atrial cell line HL-1, neonate rat heart myocytes, and an adult rat model of myocardial infarction. In electrophoretic mobility-shift assays, FoxO1 binds to the FoxO concensus site of the KATP channel subunit KIR6.1 promoter. In primary atrial culture, targeting FoxO1 and FoxO3 with siRNA specifically reduces mRNA expression of FoxO1 and -O3 and KIR6.1. Western blots, confocal immunofluorescence, and quantitative RT-PCR was applied for measuring expression of 10 Fox, 6 KATP channel subunits, and 12 metabolic genes. FoxF2, -O1, and -O3 strongly associate with expression of KATP channel subunits (in particular, KIR6.1, SUR1A and SUR2B) in different heart tissues and in the periinfarct zone of the left ventricle. Patch-clamp recordings demonstrate that molecular plasticity of these channels is matched by pharmacological plasticity and increased sensitivity to a metabolic challenge mimicked by the protonophore CCCP. A balance of FoxF2 and FoxO also regulates expression of at least 9 metabolic genes involved in setting the balance of glycolysis and ␤-oxidation. Bioinformatics shows that the transcriptional mechanisms are highly conserved among chicken, mouse, rat, and human, and Key Words: Fox transcription factors Ⅲ KATP channels Ⅲ metabolic genes Ⅲ myocardial infarction M etabolic adaptation is vitally important for cellular function, stress adaptation, and survival. This is particularly true in metabolically highly active tissues. In heart, 1 brain, 2 kidney, 3 adipose tissue, 4 muscle, 5 and blood vessels, 6 the ATP-dependent potassium channels (KATP channels) emerge as the most important sensors of cellular energy status. 7 During metabolic stress, these heterooctameric channels open in response to an increased cytoplasmic ADP/ATP ratio, thereby hyperpolarizing the cell and reducing the calcium influx and metabolic demand. 1 KATP channels protect cardiac myocytes in pathophysiological situations, 8 as well as during vigorous exercise. For example, mice with knockout of the pore-forming KATP channel subunit KIR6.2, or mice overexpressing dominant negative KIR6.1, tolerate only half of the workload compared with wild-type mice, and half of them die. 9,10 KATP channels are, however, amazingly diverse, varying in their subunit composition from one tissue to the next. The potassium channel pore consists of 4 KIR6.2 subunits in left ventricle, 11 pancreatic ␤-cells, 12 and vascular endothelium 13 and mainly of 4 KIR6.1 subunits in vascular smooth muscle. 14 The brain 2 and skeletal muscle 15 express both KIR6.1 and KIR6.2. The same cardiac tissue may change its subunit composition: subunit Kir6.1 is increasingly expressed in left ventricle following ischemia, 16 exercise, 17 or treatment with K ATP channel agonist. 18 Moreover, ...

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“…Kir6.1 mRNA and protein are specifically upregulated during myocardial infarction (Akao et al 1997). Mice lacking the Kir6.1 gene experience spontaneous ST elevation and atrioventricular block followed by sudden death .…”

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confidence: 99%

ATP-sensitive K⁺ -channel Subunits on the Mitochondria and Endoplasmic Reticulum of Rat Cardiomyocytes

Zhou

Tanaka

Sekiguchi

et al. 2005

J Histochem Cytochem.

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ATP-sensitive K+ (KATP) channel subunits on the subcellular structures of rat cardiomyocytes were studied with antibodies against Kir6.1 and Kir6.2. According to the results of Western blot analysis, Kir6.1 was strongly expressed in mitochondrial and microsome fractions, and faintly expressed in cell membrane fraction, whereas Kir6.2 was mainly expressed in the microsome fraction and weakly in cell membrane and mitochondrial fractions. Immunohistochemistry showed that Kir6.1 and Kir6.2 were expressed in the endocardium, atrial and ventricular myocardium, and in vascular smooth muscles. Immunoelectron microscopy revealed that Kir6.1 immunoreactivity was mainly localized in the mitochondria, whereas Kir6.2 immunoreactivity was mainly localized in the endoplasmic reticulum and a few in the mitochondria. Both Kir6.1 and Kir6.2 are candidates of mitochondrial KATP channel subunits. The data obtained in this study will be useful for analyzing the composition of KATP channels of cardiomyocytes and help to understanding the cardioprotective role of KATP channels during heart ischemia.

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Myocardial ischemia induces differential regulation of KATP channel gene expression in rat hearts.

Cited by 69 publications

References 34 publications

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Forkhead Transcription Factors Coordinate Expression of Myocardial KATP Channel Subunits and Energy Metabolism

ATP-sensitive K⁺ -channel Subunits on the Mitochondria and Endoplasmic Reticulum of Rat Cardiomyocytes

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Myocardial ischemia induces differential regulation of KATP channel gene expression in rat hearts.

Cited by 69 publications

References 34 publications

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Forkhead Transcription Factors Coordinate Expression of Myocardial KATP Channel Subunits and Energy Metabolism

ATP-sensitive K+ -channel Subunits on the Mitochondria and Endoplasmic Reticulum of Rat Cardiomyocytes

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ATP-sensitive K⁺ -channel Subunits on the Mitochondria and Endoplasmic Reticulum of Rat Cardiomyocytes