Taken together, the present findings are the first to establish CaMKII as a fundamental component of a cascade of events integrating the NCX, the SR, and mitochondria that promote cellular apoptosis and necrosis in irreversible I/R injury.

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 Ϸ40%, 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 ( Key Words: angiotensin II Ⅲ CaMKII Ⅲ apoptosis Ⅲ reactive oxygen species E xperimental evidence indicates that a critical factor in the transition from compensated to noncompensated cardiac hypertrophy is myocyte cell loss by apoptosis. 1 The circulating levels of Ang II are increased in heart failure and may constitute one of the major causes of cell death in this transition. 2 The apoptotic effects of Ang II have been reported to be mediated by different signaling molecules, eg, Ca 2ϩ , protein kinase (PK)C-␦, p38 mitogen-activated protein kinase (p38MAPK), or reactive oxygen species (ROS). [2][3][4][5] Recent reports have shown that activation of the multifunctional Ca 2ϩ /calmodulin-dependent protein kinase (CaMK)II is a common intermediate of diverse death stimuli-induced apoptosis in cardiac cells. 6 Supporting these results, we have demonstrated that CaMKII activation is a critical event in the signaling cascade that leads to apoptosis and necrosis occurring in reperfusion injury. 7 More importantly, we and others have shown that Ang II-induced apoptosis is caused by an increase in CaMKII activity mediated by ROS. 8,9 Recent experimental evidence further indicated that ROS-induced oxidation of methionine residues sustains CaMKII activity in the absence of Ca 2ϩ /calmodulin (Ca 2ϩ /CaM). However, this action requires previous binding of Ca 2ϩ /CaM to expose the autoinhibitory domain of CaMKII for oxidation. 8 Although these experiments suggest the concept that ROS can reset the Ca 2ϩ dependence of CaMKII activation, this possibility has never been tested. Moreover, other findings have pointed to the role of phosphatase inhibition in ROS-induced CaMKII activation. 10 In spite of these important achievements in the understanding of the proapoptotic molecules activated by Ang II, the signaling cascade whereby the peptide produces apoptosis remains uncer- The results presented herein, using pharmacological tools and genetic manipulation, show that species with opposite inotropic response to acute Ang II administration share a common apoptotic pathway triggered by the sustained stimulation wit...

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