Biomedical subjects

Taro Date

Publications and source records attributed to Taro Date.

24 records · Page 2Linked to original sources

PubMed2003

Differential effects of membrane and soluble Fas ligand on cardiomyocytes: role in ischemia/reperfusion injury.

Cardiomyocyte apoptosis by Fas ligand (FasL)/Fas signaling is associated with various pathophysiological conditions, such as ischemia/reperfusion injury and congestive heart failure. In this study, we tested the hypothesis that shedding of membrane FasL is a mechanism for downregulating FasL/Fas signaling and both membrane and soluble FasL are involved in cardiomyocyte hypoxia/reoxygenation (H/R) injury. We also examined the relative importance of mitochondrial damage and direct cleavage of the executioner caspases by activated initiator caspase 8 in the propagation of FasL/Fas signaling activated by either recombinant membrane FasL or H/R. We demonstrated that in neonatal rat cardiomyocytes maintained under normal culture conditions, recombinant human soluble FasL increased caspase 3 activation by twofold but did not reduce cell viability. In contrast, infection with a recombinant adenoviral vector expressing the non-cleavable human FasL (Ad2/nchFasL) resulted in cardiomyocyte death that was attenuated by soluble FasL. H/R increased the mRNA levels of both FasL and Fas and activated caspases 8, 9 and 3, indicating the activation of FasL/Fas signaling. Z-IETD.fmk and Z-LEHD.fmk, selective inhibitors for caspases 8 and 9, respectively, abolished caspase 3 activation induced by Ad2/nchFasL or H/R. Z-IETD.fmk also significantly reduced Ad2/nchFasL- or H/R-induced cardiomyocyte death. H/R potentiated membrane FasL-induced cell death. These results suggest that shedding of membrane FasL downregulates FasL/Fas signaling in cardiomyocytes and both membrane and soluble FasL contribute to H/R injury. Activation of FasL/Fas signaling by either recombinant membrane FasL under normal culture conditions or H/R causes cardiomyocyte death mainly through the mitochondrial damage/caspase 9 activation pathway.

Animals↗

PubMed2003

Various routes of septal propagation in common atrial flutter.

INTRODUCTION: Although in the treatment of common atrial flutter, the isthmus between the tricuspid valve annulus and the eustachian ridge is often chosen as the site for conduction block by radiofrequency ablation, the precise path of the flutter circuit remains unknown. We therefore investigated the propagation of the atrial flutter wave front around the coronary sinus ostium and how its path is altered by application of radiofrequency current. METHODS AND RESULTS: To assess activation pattern, activation in the region surrounding the coronary sinus ostium was mapped using a deflectable decapolar catheter under basal conditions and while applying radiofrequency current to the septal isthmus, between the tricuspid valve annulus and the eustachian ridge. In five of eleven patients studied, the eustachian ridge side, below the coronary sinus ostium, was activated earlier, and the flutter wave exited from either the tricuspid valve annulus side or the eustachian ridge side, above the coronary sinus ostium. In four patients, a partial line of block created by applying radiofrequency current between the tricuspid valve annulus and the coronary sinus ostium or between the coronary sinus ostium and the eustachian ridge led to a shift in the direction of propagation of the flutter wave front from anterior to posterior or from posterior to anterior of the coronary sinus ostium, and prolongation of the cycle length. CONCLUSION: Application of radiofrequency current to the septal isthmus, between the tricuspid valve annulus and the eustachian ridge, can shift both the anterior and posterior propagation of flutter around the coronary sinus ostium.

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PubMed2002

Adenovirus-mediated expression of p35 prevents hypoxia/reoxygenation injury by reducing reactive oxygen species and caspase activity.

OBJECTIVE: This study aimed to examine the effects of adenovirus-mediated expression of p35, a baculovirus gene, on apoptosis induced by hypoxia/reoxygenation (H/R) in cardiomyocytes. METHODS: Neonatal rat cardiomyocytes were infected with recombinant adenoviral vectors expressing p35 (Ad2/CMVp35) or no transgene (Ad2/CMVEV) and were then subjected to H/R. Separate groups of non-infected cardiomyocytes were treated with pharmacological caspase inhibitors or antioxidants. Cell viability, apoptosis, caspase activity, and cellular reactive oxygen species (ROS) were measured using various assays. RESULTS: H/R decreased cell viability and increased cellular ROS levels, caspase activity, and cell apoptosis. Infection with Ad2/CMVp35 effectively inhibited the increase in cellular ROS levels, the activities of caspases 3 and 8, apoptosis, and cell death following H/R, whereas Ad2/CMVEV had no effect. Despite its ability to abolish the increase in caspase activity and partially inhibit apoptosis, the pan-caspase inhibitor ZVAD-fmk (100 microM) failed to significantly reduce cell death induced by H/R. N-acetyl-L-cysteine, an antioxidant, completely inhibited H/R-induced increase in cellular ROS levels, but reduced apoptosis and cell death by 30% only. CONCLUSIONS: Adenovirus-mediated expression of p35 effectively inhibits H/R-induced cardiomyocyte apoptosis by reducing cellular ROS levels and inhibiting caspase activity.

Adenoviridae↗

PubMed2002

Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1.

Hypoxia regulates expression of vascular endothelial growth factor (VEGF) by increasing its transcription and by stabilizing its mRNA. Despite the pivotal role of hypoxia-inducible factor 1 (HIF-1) in transcriptional activation of hypoxia-responsive genes, it is not known whether HIF-1 mediates hypoxia-induced stabilization of VEGF mRNA. We constructed adenoviral vectors expressing either the wild-type HIF-1 alpha (Ad2/HIF-1 alpha/FL), a constitutively stable hybrid form of HIF-1 alpha (Ad2/HIF-1 alpha/VP16), or no transgene (Ad2/CMVEV). In rat glioma (C6) cells and human cardiac, vascular smooth muscle, and endothelial cells, infection with Ad2/HIF-1 alpha/VP16 or Ad2/HIF-1 alpha/FL increased VEGF expression at both the mRNA and protein levels. Under normoxic conditions, the half-life of VEGF mRNA was 42 min in C6 cells. Hypoxia and Ad2/HIF-1 alpha/VP16 increased the half-life of VEGF mRNA to 3.3 and 2.7 h, respectively, while Ad2/CMVEV had no effect. These studies are the first to demonstrate that overexpression of HIF-1 alpha increases VEGF mRNA stability. Our results also suggest that stabilization of VEGF mRNA by hypoxia is mediated, at least in part, by HIF-1.

Adenoviridae↗

PubMed2002

Hypoxia up-regulates expression of peroxisome proliferator-activated receptor gamma angiopoietin-related gene (PGAR) in cardiomyocytes: role of hypoxia inducible factor 1alpha.

Peroxisome proliferator-activated receptors (PPAR), especially the PPARalpha and PPARgamma, are associated with an extraordinary diverse spectrum of cardiovascular diseases including hypertension, angiogenesis, cardiac hypertrophy, and atherosclerosis. PGAR (for PPAR gamma angiopoietin-related gene) is a recently identified PPAR target gene which is associated with adipose differentiation, systemic lipid metabolism, energy homeostasis, and possibly angiogenesis. We report here that WY-14643, a selective PPARalpha ligand up-regulated PGAR expression in neonatal rat cardiomyocytes. In parallel to activating the expression of vascular endothelial growth factor and glucose transporter-4, hypoxia increased PGAR mRNA levels. PGAR expression was also increased by desferrioxamine and CoCl(2), but not by sodium cyanide, results consistent with the pharmacological features of hypoxia-responsive genes. These studies are the first to demonstrate that hypoxia increases the mRNA levels of a PPAR target gene in cardiomyocytes. Furthermore, infection with adenoviral vectors encoding the wild-type or a hybrid form of HIF-1alpha highly increased PGAR mRNA levels. In contrast, neither hypoxia nor overexpression of HIF-1alpha affected the mRNA levels of PPARalpha, PPAR gamma, and muscle carnitine palmitoyltransferase, a known PPARalpha target gene. These results suggest that hypoxic activation of PGAR expression is likely mediated by HIF-1 but not the PPARalpha/RXR pathway.

Angiogenesis Inducing Agents↗

PubMed2002

Effect of low-dose isoproterenol infusion on left atrial appendage function soon after cardioversion of chronic atrial tachyarrhythmias.

BACKGROUND: Cardioversion of chronic atrial fibrillation or atrial flutter to sinus rhythm is often associated with transient atrial mechanical dysfunction, i.e. 'atrial stunning', which may increase the risk of subsequent thromboembolic events. We hypothesized that, because of its positive inotropic action, a low-dose isoproterenol infusion might improve postcardioversion atrial mechanical function. METHOD: Eighteen patients (15 male, three female; 12 atrial fibrillation, six atrial flutter; mean age 65+/-10 years) exhibiting atrial postcardioversion stunning were included in the study. Isoproterenol was infused for 10 min at a dose sufficient to increase the heart rate by about 10%. Using transesophageal echocardiography, both the left atrial appendage emptying/filling flow velocity and function (fractional area change) were examined at baseline, before isoproterenol (immediately after cardioversion) and after isoproterenol. RESULTS: With infusion of 0.005-0.008 microg/kg/min isoproterenol, heart rate increased by 11.1+/-2.9%, and left atrial appendage emptying velocity, which was diminished following cardioversion, increased significantly (P<0.001) (baseline, before and after isoproterenol: 41.1+/-18.0, 20.3+/-8.5 and 27.3+/-9.6 cm/s, respectively). No major complications were associated with isoproterenol infusion. CONCLUSIONS: Short-term infusion of low-dose isoproterenol improved atrial function after cardioversion of chronic atrial fibrillation and atrial flutter.

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