CaMKII inhibition protects against necrosis and apoptosis in irreversible ischemia–reperfusion injury

Abstract

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.

Differential Integration of Ca2+-Calmodulin Signal in Intact Ventricular Myocytes at Low and High Affinity Ca2+-Calmodulin Targets

“…Again our modeling and experimental data suggest that under normal conditions there is little progressive CaMKII autophosphorylation, unless the phosphatases are inhibited (37,48). This does not preclude functional importance of CaMKII autophosphorylation in the heart, but this may be most important in pathophysiological setting like acidosis, ischemia/reperfusion (13,49), or heart failure (50,51). CaMKII can also phosphorylate many targets, and the lifetime and integration of those phosphorylation effects are controlled by a balance of kinase and phosphatase reactions, and these may differ among different targets and in different cellular environments (where local phosphatase and kinase activities vary).…”

“…It is well established that the activated form of CaM, Ca 2ϩ -CaM, modulates the function of various downstream targets (4) including ion channels (5)(6)(7) and enzymes such as CaM-dependent protein kinase II (CaMKII) (8), myosin light chain kinase (MLCK) (9), nitricoxide synthase (10), and CaM-dependent phosphatase calcineurin (CaN) (11), which play central roles in diverse cellular processes. For example, CaMKII is implicated in regulation of the excitation-contraction coupling (8,12) and apoptosis in the heart (13,14), whereas CaN dephosphorylates transcription factors to regulate gene expression related to cardiac hypertrophy and heart failure (11). Despite the wide appreciation of the importance of Ca, CaM, and CaM targets on cardiac myocyte function, an intriguing question remains unsolved about how CaM and its target proteins differentiate Ca 2ϩ signals to ensure the appropriate cellular responses in the heart.…”

Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways

“…Activated CaMKII then enables apoptosis through at least 3 pathways, all of which are necessary for cell death: (a) activation of JNK, which induces Fas; (b) stimulation of calcium uptake by the mitochondria, leading to outer mitochondrial membrane permeabilization and release of apoptogens as well as Δψ m ; and (c) activation of STAT1, which has previously been shown to promote apoptosis in diverse cell types by a number of transcriptional and perhaps nontranscriptional mechanisms (54). Although studies in other cells have shown that proapoptotic mitochondrial dysfunction can be triggered by the mitochondrial uptake of ER-released calcium in the setting of ER stress (41) and that CaMKII can play roles in apoptosis (55)(56)(57)(58)(59), the current study is the first to our knowledge to link these pathways into an integrated model of apoptosis and to show that CaMKII is essential for mitochondrial calcium uptake. Another important point relates to our finding that neither induction of Fas (data not shown) nor mitochondrial depolarization was dependent on STAT1.…”

Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism

“…The infarct size was measured through the triphenyltetrazolium chloride (TTC) technique as described previously [26]. At the end of reperfusion, the hearts were first perfused with TTC 1% and then frozen at -20 °C for 1 h. Then, hearts were cut into six slices and stored with formaldehyde 10% for 48 h before measuring the infarct area using the software imageJ.…”