CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
CAMKII MEDIATES ANGIOTENSIN II-INDUCED CARDIOMYOCYTES APOPTOSIS. ROLE OF CA2+, ROS AND P38MAPK
Autor/es:
PALOMEQUE, JULIETA; LUCIANA SAPIA; CARLOS VALVERDE; JORGE OMAR VELEZ RUEDA; SALAS, MARGARITA A; ALICIA MATTIAZZI; MARTIN G. VILA PETROFF
Lugar:
Athens, May 28 - May 31
Reunión:
Congreso; XXVIII European Section Meeting of the Internacional Society for Heart Research; 2008
Institución organizadora:
Seccion Europea de la Internacional Society for Heart Research
Resumen:
Angiotensin II (Ang II) increases Ca2+i inducing a positive inotropic effect in feline heart. In the rat heart Ang II induces a negative inotropic effect without changes in Ca2+i and associated to p38 activation. On other hand, CaMKII is linked to Ca2+ and cell death. Given that, in heart failure the activity of this kinase and the levels of Ang II are increased, our aim was to establish the nexus between Ang II and CaMKII in the signaling pathway to cell death, clarifying the underlying mechanisms in two species where Ang II exerts opposite effects on contractility. For this purpose we used cardiomyocytes from cats and rats cultured for 24h with and without 1µM Ang II. We determined cell viability, CaMKII activity, Ca2+i and ROS. Ang II evoked ≈ 30% mortality in both species at the expense of apoptosis (TUNEL staining and decrease in the Bax/Bcl-2 ratio) and necrosis (increase in LDH). This mortality was associated with 32.6±5.6% increase in P-CaMKII and a concomitant increase in P-Thr17. The Ang II treatment did not affect diastolic Ca2+, systolic Ca2+ nor the SR Ca2+ load. However, Ang II significantly enhanced ROS production (15.0±1.5). Inhibitors of CaMKII (KN-93 1uM), of NADPH oxidase (DPI 10uM), of ROS (MPG 1uM) and of p38 (SB 203580 10uM) prevented Ang II-induced cell death. Moreover, p38 overexpression exacerbated the mortality produced by Ang II. In conclusion, the results indicate a Ca2+ independent Ang II-induced cell death. Moreover, the increased ROS, CaMKII and p38 activation would be putative factors in the apoptotic pathway initiated by the peptide. The novel role of CaMKII as a mediator of Ang II-induced cell death without changes in Ca2+ argues in favor of a Ca2+ independent activation of the kinase. We speculate that the Ang II induced increase in ROS would be the trigger for CaMKII activation which in turn actives p38 culminating in cell death.
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