The ␦ B and ␦ C splice variants of Ca 2؉ /calmodulin-dependent protein kinase II (CaMKII), which differ by the presence of a nuclear localization sequence, are both expressed in cardiomyocytes. We used transgenic (TG) mice and CaMKII expression in cardiomyocytes to test the hypothesis that the CaMKII␦ C isoform regulates cytosolic Ca 2؉ handling and the ␦ B isoform, which localizes to the nucleus, regulates gene transcription. Phosphorylation of CaMKII sites on the ryanodine receptor (RyR) and on phospholamban (PLB) were increased in CaMKII␦ C TG. This was associated with markedly enhanced sarcoplasmic reticulum (SR) Ca 2؉ spark frequency and decreased SR Ca 2؉ content in cardiomyocytes. None of these parameters were altered in TG mice expressing the nuclear-targeted CaMKII␦ B . In contrast, cardiac expression of either CaMKII␦ B or ␦ C induced transactivation of myocyte enhancer factor 2 (MEF2) gene expression and up-regulated hypertrophic marker genes. Studies using rat ventricular cardiomyocytes confirmed that CaMKII␦ B and ␦ C both regulate MEF2-luciferase gene expression, increase histone deacetylase 4 (HDAC4) association with 14-3-3, and induce HDAC4 translocation from nucleus to cytoplasm, indicating that either isoform can stimulate HDAC4 phosphorylation. Finally, HDAC4 kinase activity was shown to be increased in cardiac homogenates from either CaMKII␦ B or ␦ C TG mice. Thus CaMKII␦ isoforms have similar effects on hypertrophic gene expression but disparate effects on Ca 2؉ handling, suggesting distinct roles for CaMKII␦ isoform activation in the pathogenesis of cardiac hypertrophy versus heart failure.is the predominant isoform of CaMKII in the heart. Splice variants differing in the presence of a nuclear localization sequence (NLS) show distinct subcellular targeting to either cytoplasmic or nuclear compartments (1-3). The CaMKII␦ B isoform contains an 11 amino acid NLS that is absent from ␦ C . Thus CaMKII heteromers comprised predominantly of ␦ B subunits localize to the nucleus while those with predominantly ␦ C localize to the cytoplasm (1-3). We recently demonstrated that both ␦ B and ␦ C CaMKII are activated in response to pressure overload induced by thoracic aortic banding but that expression of these isoforms is differentially regulated (4). The possibility that there are discrete roles for these two isoforms in regulating Ca 2ϩ homeostasis and gene transcription has not yet been explored.CaMKII has long been implicated as a regulator of Ca 2ϩ homeostasis and excitation-contraction (E-C) coupling in ventricular myocytes. This enzyme has been shown to phosphorylate proteins involved in sarcoplasmic reticulum (SR) Ca 2ϩ handling including the cardiac ryanodine receptors (RyR2) and phospholamban (PLB) (4 -10). Phosphorylation of the RyR2 appears to alter its channel open probability (9 -11) while phosphorylation of PLB by CaMKII can regulate SR Ca 2ϩ uptake (10, 12). Altered intracellular Ca 2ϩ handling plays an important role in the pathogenesis of heart failure with changes in Ca 2ϩ cycling pr...
Background-Women are at a higher risk for bleeding/vascular complications (VC) related to cardiovascular procedures.Although the overall incidence of percutaneous coronary intervention (PCI)-related bleeding/VC has declined, the impact of this decline, specifically in women, is unknown. Methods and Results-We studied 13 653 female and 32 334 male consecutive cases, from 2002 to 2007, in the Northern New England PCI Registry. We sought to (1) compare absolute rates of bleeding/VC in women and men over time, (2) define predictors of bleeding/VC in women and men undergoing PCI, and (3) trend the impact of female gender in predicting bleeding/VC over time. Bleeding/VC was defined as any access-site vessel injury requiring surgical intervention or bleeding requiring transfusion. The overall risk of bleeding/VC was significantly higher in women versus men (4.5Ϯ1.3% versus 1.6Ϯ0.5%; PϽ0.004). Over time, there was a significant (PϽ0.001) 50% decrease in absolute bleeding/VC rates in both women and men. After adjustment for baseline differences, female gender remained a significant predictor of increased risk in 2007 (odds ratio, 2.6; 95% CI, 1.74 to 3.91). Independent predictors of increased risk of bleeding/VC in women included older age, shock, renal failure, presentation with non-ST-elevation myocardial infraction and larger sheath sizes, whereas the use of fluoroscopy-guided access, closure devices, history of dyslipidemia or prior PCI, and use of bivalirudin were protective. Conclusion-Women undergoing PCI have had a significant decline in bleeding/VC rates during the last 6 years. Despite the improvement in procedural safety, female gender continues to be associated with a Ͼ2-fold risk of bleeding/VC compared with men. (Circ Cardiovasc Intervent. 2009;2:423-429.)
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