Angiotensin II-Induced Oxidative Stress Resets the Ca(2+) Dependence of Ca(2+)-Calmodulin Protein Kinase II and Promotes a Death Pathway Conserved Across Different Species

作者：Palomeque Julieta; Velez Rueda Omar; Sapia Luciana; Valverde Carlos A; Salas Margarita; Vila Petroff Martin; Mattiazzi Alicia

来源：Circulation Research, 2009, 105(12): 1204-+.

DOI：10.1161/CIRCRESAHA.109.204172

• angiotensin II
• CaMKII
• apoptosis
• reactive oxygen species

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 mu mol/L) reduced cat/rat myocytes viability by approximate to 40%, in part, because of apoptosis (TUNEL/caspase-3 activity). In both species, apoptosis was associated with reactive oxygen species (ROS) production, Ca(2+)/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 H(2)O(2), even in the presence of the Ca(2+) chelator BAPTA-AM, in myocytes and in EGTA-Ca(2+)-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 Ca(2+) concentrations, suggesting a new mechanism by which ROS reset the Ca(2+) dependence of CaMKII to extremely low Ca(2+) levels. (Circ Res. 2009; 105: 1204-1212.)

• 出版日期2009-12-4