ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

TheSCN5Agene encodes the &agr; subunitof the human heart sodium channel (hH1), which plays a critical role incardiac excitability. Mutations ofSCN5Aunderlie Brugada syndrome, aninherited disorder that leads to ventricular fibrillation and sudden death.This study describes changes in cellular localization and functionalexpression of hH1 in a naturally occurringSCN5Amutation (R1432G) reported forBrugada syndrome. Using patch-clamp experiments, we show that there is anabolition of functional hH1 expression in R1432G mutants expressed in humantsA201 cells but not inXenopusoocytes. In tsA201 cells, a conservative positively charged mutant, R1432K,produced sodium currents with normal gating properties, whereas othermutations at this site abolished functional sodium channel expression.Immunofluorescent staining and confocal microscopy showed that the wild-type&agr; subunit expressed in tsA201 cells was localized to the cell surface,whereas the R1432G mutant was colocalized with calnexin within the endoplasmicreticulum. The &bgr;1subunit was also localized to thecell surface in the presence of the &agr; subunit; however, in its absence,the &bgr;1subunit was restricted to a perinuclearlocalization. These results demonstrate that the disruption ofSCN5Acell-surface localization is onemechanism that can account for the loss of functional sodium channels inBrugada syndrome. The full text of this article is available athttp://www.circresaha.org.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

TheHCN family of ion channel subunits underlies the currentsIfin heart andIhandIqin thenervous system. In the present study, we demonstrate that minK-related peptide1 (MiRP1) is a &bgr; subunit for the HCN family. As such, it enhances proteinand current expression as well as accelerating the kinetics of activation.Because MiRP1 also functions as a &bgr; subunit for the cardiac delayedrectifierIKr,these results suggest that this peptide may have the unique role of regulatingboth the inward and outward channels that underlie cardiac pacemaker activity.The full text of this article is available athttp://www.circresaha.org.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Insulin-likegrowth factor (IGF)-1 activates intracellular signaling pathways and regulatesmyocardial structure and function. This study used DNA microarray to definethe effects of IGF-1 on gene expression in cardiomyocytes. Despite DNAmicroarray becoming a popular tool for profiling gene expression, thespecificity of DNA microarray results is rarely addressed. Our data showedthat the specificity of a DNA microarray study can be increased by repetitiveexperiments and by excluding minimally expressed genes. In this study, thefalse-positive rates were reduced to <0.2%. Future DNA microarray studiesshould incorporate a proper strategy to minimize false-positive results. IGF-1modulates the expression of genes in 17 functional categories, but most genesclustered around the regulation of intracellular signaling, cell cycle,transcription/translation, cellular respiration and mitochondrial function,cell survival, ion channels and calcium signaling, and humoral factors. Tofurther explore whether extracellular signal-regulated kinase (ERK) andphosphatidylinositol (PI) 3 kinase specifically regulate different sets ofgenes, the effects of IGF-1 were inhibited with PD98059 or LY294002. Theresults showed that the majority of genes regulated by IGF-1 requiredactivation of both ERK and PI 3 kinase. Thus, PI 3 kinase and ERK coordinatelymediate the transcriptional regulatory effects of IGF-1 in cardiac musclecells. These findings provide novel insight into how IGF-1 signaling modulatesthe programming of cardiac muscle geneexpression.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Endothelin-1(ET-1) acts not only as a growth-promoting peptide but also as a potentsurvival factor against myocardial cell apoptosis. However, the signalingpathways leading to myocardial cell protection by ET-1 are poorly understood.Using a culture system of primary cardiac myocytes derived from neonatal rats,we show in the present study that ET-1 almost completely blocked the hydrogenperoxide-induced increase in the percentage of TdT-mediated dUTP-biotinnick-end labeling-positive myocytes. Apoptosis inhibition by ET-1 wasconfirmed by cytofluorometric analysis as well as by examination of the ladderformation, morphological features, and caspase-3 cleavage. We have found thatET-1 converts the nuclear factor of activated T lymphocytes (NFATc) in cardiacmyocytes into high-mobility forms and translocates cytoplasmic NFATc to thenuclei. In addition, ET-1 stimulates the interaction between NFATc and thecardiac-restricted zinc-finger protein GATA4 in these cells. Theimmunosuppressants cyclosporin A and FK506, which antagonize calcineurin,negated the inhibitory effect of ET-1 on apoptosis. Calcineurin activation denovo was sufficient to inhibit hydrogen peroxide-induced apoptosis. ET-1induced the expression of an antiapoptotic protein bcl-2 in cardiac myocytesin a cyclosporin A-dependent manner, but it did not alter the expression ofbax. Cyclosporin A also attenuated the ET-1-stimulated transcription of thebcl-2 gene in these cells. These findings demonstrate that the calcineurinpathway is required for the inhibitory effect of ET-1 on oxidantstress-induced apoptosis in cardiacmyocytes.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID