Cardioplegia and angiotensin II receptor antagonists modulate signal transducers and activators of transcription activation in neonatal rat myocytes.

A crescente necessidade de informação para a tomada de decisões dos gestores do setor do transporte urbano de passageiros obriga a desenvolver sistemas para o cálculo, análise e controle de custos que permitam conhecer de forma acurada os mecanismos de formação dos seus preços internos. Nesse contexto, a medida do rendimento adquire um interesse especial quando é comparada a parâmetros e padrões significativos, que permitam aplicar técnicas de benchmarking para melhorar a gestão econômica do serviço. Com esses fins, entende-se que a geração de medidas representativas de padrões coletivos de comportamento constitui-se em uma ferramenta útil para orientar a ação de gestores e administradores públicos. E, como conseqüência, nós apresentamos à Asociación de Empresas de Transporte Urbano Colectivo (ATUC), na Espanha, um projeto para a criação de um Observatório de Custos que possa constituir-se em um importante ponto de referência para as empresas de transporte urbano de passageiros. Palavras-chave: Custos. Financiamento. Transporte urbano de passageiros. * Trabalho apresentado no XIII Congresso Brasileiro de Custos, realizado em Belo Horizonte – MG, no período de 30 de outubro a 01 de novembro 2006.The possibility of providing more complete and detailed data about passenger transport enterprises management justifies the development of analysis and cost control systems that provide precise and rigorous knowledge about internal price formation mechanisms. In this framework, measurement of performance is especially relevant when compared with some other significant reference parameters that allow the use of benchmarking in order to improve the economic management of the service. To this end, we consider it especially useful for the ATUC (Asociación de Empresas de Transporte Urbano Colectivo, i.e., the Association of Collective Urban Transport Companies) to provide a service that establishes measures which represent actual behaviour patterns, that enhances the knowledge of the reality of the sector and that generates a spirit of self-improvement in their associates. We presented a project to ATUC proposing the establishment of a Costs Observatory that can become a significant reference point for passenger transport companies. Key words: Costs. Funding. Urban Passenger Transport.Las crecientes necesidades de información para la gestión y la toma de decisiones de los agentes que operan en el sector del transporte urbano de pasajeros, obliga a desarrollar sistemas para el cálculo, análisis y control de costes que permitan un conocimiento riguroso de los mecanismos de formación de sus precios internos. En dicho marco, la medida del rendimiento adquiere especial interés cuando entra en comparación con parámetros y estándares significativos, que permitan aplicar técnicas de benchmarking para mejorar la gestión económica del servicio. A tales efectos, entendemos que la generación de medidas representativas de patrones colectivos de comportamiento, constituye una herramienta de gran utilidad para orientar la acción de gestores y administradores públicos. Y, en consecuencia, en España, y en el seno de la Asociación de Empresas de Transporte Urbano Colectivo (ATUC), estamos desarrollando un proyecto para la creación de un Observatorio de Costes que pueda constituirse en significativo punto de referencia para las empresas de transporte urbano de viajeros. Palabras clave: Costes. Financiación.Transporte urbano de viajeros

Cardioplegia and angiotensin II receptor antagonists modulate signal transducers and activators of transcription activation in neonatal rat myocytes.

Previous investigations have shown that the signal transducers and activators of transcription (STATs) signaling pathway play an important role in the modulation of apoptosis after ischemia and reperfusion. The mechanism for this enhanced cardioprotection is unknown, but we believe that alterations STATs may play a role. To investigate this hypothesis, we examined the effects of angiotension II type 1 (AT1) and angiotension II type 2 (AT2) receptor antagonist added to cardioplegia on the downstream response of different STATs, connected with proinflammatory pathways (STAT2, STAT5) and prohypertrophic and antiapoptotic pathways (STAT3). Isolated, nonworking hearts (n = 3 per group) from neonatal rats were perfused aerobically (4°C) for 20 min in the Langendorff mode with the modified St. Thomas' Hospital no. 2 (MSTH2) cardioplegic solution (Group 1), the MSTH2 cardioplegic solution + AT1 receptor antagonist (Group 2), and MSTH2 cardioplegic solution + AT2 receptor antagonist (Group 3). Thus, myocytes were isolated by enzymatic digestion, and STAT2, STAT3, and STAT5 were investigated in Western blot studies. Times to arrest after cardioplegia were 8-12 s for all groups. Total cardioplegia delivery volume was about 300 mL for the 20 min. Perfusion with the MSTH2 cardioplegic solution supplemented with AT1 receptor antagonist (Group 2) induced a significant reduction in STAT2 and STAT5 tyrosine phosphorylation (-58 and -63%, respectively, vs. Group 1, P < 0.05). Conversely, STAT2 and STAT5 activation were unaffected by perfusion with the MSTH2 cardioplegic solution supplemented with AT2 receptor antagonist (Group 3). The decreased activation of STAT2 and STAT5 observed in Group 2 was accompanied by reduction of interleukin-1β (-57% in Group 2 vs. Group 1, P < 0.05). There were no significant differences in STAT3 phosphorylation among all groups. Only the addition of AT1 receptor antagonist to MSTH2 cardioplegia significantly decreases the inflammatory response of the neonatal rat cardiomyocytes without affecting antiapoptotic influence provided by tyrosine phosphorylation of STAT3. AT1 receptor antagonist added to cardioplegia represents an additional modality for enhancing myocardial protection during cardiac surgery and could contribute to optimize the ischemia tolerance of the pediatric heart

Impaired JAK2-induced activation of STAT3 in failing human myocytes.

Although angiotensin (Ang)II-induced Janus-activated kinase (JAK)2 phosphorylation was reported to be enhanced in failing human cardiomyocytes, the downstream balance between cardio-protective (signal transducer and activator of transcription-STAT3) and the pro-inflammatory (STAT2 and STAT5) response remains unexplored. Therefore STATs phosphorylation and putative genes overexpression following JAK2 activation were investigated in isolated cardiomyocytes obtained from failing human hearts (n = 16), and from non-failing(NF) hearts of humans (putative donors, n = 6) or adult rats. In NF myocytes Ang II-induced JAK2 activation was followed by STAT3 phosphorylation (186 \ub1 45% at 30 min), with no STAT2 or STAT5 response. The associated B cell lymphoma (Bcl)-xL overexpression (1.05 \ub1 0.39 fold) was abolished by both JAK2 and extracellular signal-regulated kinase (ERK)1/2 inhibitors (AG490, 10 \u3bcM, and PD98059, 30 \u3bcM, respectively), whereas Fas ligand (Fas-L) response (0.91 \ub1 0.21 fold) was inhibited only by p38MAPK antagonism (SB203580, 10 \u3bcM). In failing myocytes Ang II-induced JAK2 activation was followed by STAT2 (237 \ub1 38%) and STAT5 (222 \ub1 31%) phosphorylation, with no STAT3 response. No changes in Bcl-xL expression were observed, and the associated Fas-L gene overexpression (1.14 \ub1 0.27 fold) being abolished by p38 mitogen-activated protein kinase (MAPK) antagonism. The altered JAK2 induced STATs response in human failing cardiomyocytes may be of relevance for the progression of cardiac dysfunction in heart failure

Angiotensin II Type 1 (AT1) Receptor Antagonist Not Cardioplegia Temperature Regulates Activation of Pro-Inflammatory Signal Transducers and Activators of Transcription (STAT) Proteins in Neonatal Rat Myocytes.

Background:Cardioplegic arrest even if controlled is a model of ischaemia/reperfusion (I/R) injury and results in the death of irreplaceable cardiac myocytes by a programme cell death or apoptosis. STAT signaling pathways play an important role in the modulation of apoptosis after ischemia and reperfusion. AT1 receptor antagonist added to cardioplegia could represent an additional modality for enhancing myocardial protection during cardioplegic arrest. To test that hypothesis, we studied the effect of AT1 receptor antagonism and cardioplegia temperature perfusion on STATs modulation during cardioplegic arrest in neonatal rat hearts.Methods:Isolated, nonworking hearts (n = 4 per group) from neonatal rats were perfused aerobically in the Langendorff mode accordingly following scheme: DMEM solution (Group 1); cold (4\ub0C) modified St. Thomas' Hospital no. 2 (MSTH2) cardioplegic solution (Group 2); cold (4\ub0C) MSTH2 cardioplegic solution plus AT1 antagonist (Valsartan) (Group 3); warm (34\ub0C) MSTH2 cardioplegic solution (Group 4). Thus, myocytes were isolated by enzymatic digestion, and STAT1, STAT2, STAT3, and STAT5 were investigated in Western blot studies.Results:Times to arrest after cardioplegia were 6-10 seconds for all groups with exception of Group 1 (spontaneously arrest after16 seconds). Total cardioplegia delivery volume was about 300 mL in 15 minutes. Perfusion with cold MSTH2 supplemented with AT1 receptor antagonist (Group 3) induced a significant reduction in STAT1, STAT2 and STAT5 tyrosine phosphorylation versus other groups (P < 0.05). The decreased activation of STAT1, STAT2 and STAT5 observed in Group 3 was accompanied by reduction of interleukin-1\u3b2 (P < 0.05). Differently, STAT3 activation was significantly reduced in Groups 1 and 4 (P < 0.05).Conclusions:Only perfusion with AT1 receptor antagonist supplemented cold MSTH2 significantly decreases the inflammatory response of the neonatal rat cardiomyocytes without affecting antiapoptotic influence provided by activation of STAT3. Therefore, AT1 receptor antagonist could play a pivotal role in cytoprotective effect and cardiac recovery in neonates and infants

Effects of angiotensin II type 1 receptor antagonist and temperature on prolonged cardioplegic arrest in neonatal rat myocytes.

Cardioplegic arrest is a model of ischemia/reperfusion injury and results in the death of irreplaceable cardiac myocytes by a programmed cell death or apoptosis. Signal transducers and activators of transcription (STAT) signaling pathways play an important role in the modulation of apoptosis after ischemia and reperfusion. Angiotensin II type 1 (AT1) receptor antagonist added to cardioplegia could represent an additional modality for enhancing myocardial protection during cardioplegic arrest. To test that hypothesis, we studied the effect of AT1 receptor antagonism and cardioplegia temperature perfusion on STATs modulation during cardioplegic arrest in neonatal rat hearts. Isolated, nonworking hearts (n = 4 per group) from neonatal rats were perfused aerobically in the Langendorff mode according to the following scheme: Dulbecco's Modified Eagle's Medium solution (Group 1); cold (4°C) modified St. Thomas' Hospital no. 2 (MSTH2) cardioplegic solution (Group 2); cold (4°C) MSTH2 cardioplegic solution plus AT1 antagonist (Valsartan) (Group 3); and warm (34°C) MSTH2 cardioplegic solution (Group 4). Thus, myocytes were isolated by enzymatic digestion, and STAT1, STAT2, STAT3, and STAT5 were investigated in Western blot studies. Times to arrest after cardioplegia were 6-10 s for all groups with the exception of Group 1 (spontaneous arrest after 12-16 s). Total cardioplegia delivery volume was about 300 mL in 15 min. Perfusion with cold MSTH2 supplemented with AT1 receptor antagonist (Group 3) induced a significant reduction in STAT1, STAT2, and STAT5 tyrosine phosphorylation versus other groups (P < 0.05). The decreased activation of STAT1, STAT2, and STAT5 observed in Group 3 was accompanied by reduction of interleukin-1β (P < 0.05). On the other hand, STAT3 activation was significantly reduced in Groups 1 and 4 (P < 0.05). Only perfusion with AT1 receptor antagonist supplemented with cold MSTH2 significantly decreases the inflammatory response of the neonatal rat cardiomyocytes without affecting antiapoptotic influence provided by activation of STAT3. Therefore, AT1 receptor antagonist could play a pivotal role in cytoprotective effect and cardiac recovery in neonates and infants