Angiotensin II-induced oxidative stress resets the Ca2+ dependence of Ca2+-calmodulin protein kinase II and promotes a death pathway conserved across different species

4. PALOMEQUE J, RUEDA OV, SAPIA L, VALVERDE CA, SALAS M, PETROFF MV, MATTIAZZI A

CIRCULATION RESEARCH

LIPPINCOTT WILLIAMS & WILKINS

Año: 2010 vol. 105 p. 1204 - 1212

0009-7330

Rationale: Angiotensin (Ang) II–induced apoptosis was reported to be mediated by different signaling molecules. Whether these molecules are either interconnected in a single pathway or constitute different and alternative cascades by which Ang II exerts its apoptotic action, is not known. Objective: To investigate in cultured myocytes from adult cat and rat, 2 species in which Ang II has opposite inotropic effects, the signaling cascade involved in Ang II–induced apoptosis. Methods and Results: Ang II (1 _mol/L) reduced cat/rat myocytes viability by _40%, in part, because of apoptosis(TUNEL/caspase-3 activity). In both species, apoptosis was associated with reactive oxygen species (ROS) production, Ca2_/calmodulin–dependent protein kinase (CaMK)II, and p38 mitogen-activated protein kinase(p38MAPK) activation and was prevented by the ROS scavenger MPG (2-mercaptopropionylglycine) or the NADPH oxidase inhibitor DPI (diphenyleneiodonium) by CaMKII inhibitors (KN-93 and AIP [autocamtide 2-related inhibitory peptide]) or in transgenic mice expressing a CaMKII inhibitory peptide and by the p38MAPK inhibitor, SB202190. Furthermore, p38MAPK overexpression exacerbated Ang II–induced cell mortality. Moreover, although KN-93 did not affect Ang II–induced ROS production, it prevented p38MAPK activation. Results further show that CaMKII can be activated by Ang II or H2O2, even in the presence of the Ca2_ chelator BAPTA-AM, in myocytes and in EGTA-Ca2_–free solutions in the presence of the calmodulin inhibitor W-7 in in vitro experiments. Conclusions: (1) The Ang II–induced apoptotic cascade converges in both species, in a common pathway mediated by ROS-dependent CaMKII activation which results in p38MAPK activation and apoptosis. (2) In the presence of Ang II or ROS, CaMKII may be activated at subdiastolic Ca2_ concentrations, suggesting a new mechanism by which ROS reset the Ca2_ dependence of CaMKII to extremely low Ca2_ levels. (Circ Res. 2009;105:1204-1212.)