Dual role of Calcium-Calmodulin dependent Kinase II signaling in cardiac ischemia and reperfusion

VALVERDE CA

Salto Grande

Simposio; Latin American Crosstalk in Biophysics and Physiology; 2015

Sociedad Argentina de Biofísica y Seccional Biofísica de la Sociedad Uruguaya de Biociencias

Extensive experimental data indicate thathearts submitted to an ischemic insult are prone to cardiac dysfunction andarrhythmias, both associated with altered calcium cycling, particularly duringreperfusion. Thus, the early phase of reperfusion is of particular clinical relevancefor reducing the damage of the ischemic heart. Previous results from ourlaboratory were the first to describe a cascade of events triggered at the onsetof reperfusion involving the activation of two main ionic exchangers, Na+/H+and Na+/Ca2+. These events are related to activation ofthe calcium and calmodulin dependent kinase II (CaMKII delta isoform), which phosphorylatesamong several targets, the sarcoplasmic reticulum (SR) protein phospholamban(PLN), a main regulator of SERCA2a (sarcoplasmic reticulum Ca2+-ATPase2a), and the SR calcium channels (ryanodine receptors type 2, RyR2).Phosphorylation of Thr17 residue of PLN at the beginning ofreperfusion precedes and is necessary for the recovery of relaxation,contractility and intracellular Ca2+ handling in the reversibleischemia (brief) and reperfusion (I/R) injury, also known as stunned heart. Onthe other hand, we described that hearts submitted to prolonged ischemiainitiates an apoptotic/necrotic pathway mediated by CaMKII-dependentphosphorylations at the SR (Thr17-PLN and Ser2814-RyR2),which involves the reverse NCX mode and the mitochondria as trigger and endeffectors, respectively, of the cascade. CaMKII is also involved in reperfusionarrhythmias due to SR Ca2+ leak through RyR2, induced byphosphorylation of RyR2, which propagates as Ca2+ waves. These Ca2+waves depolarize cell membrane (through the Na+/Ca2+exchanger) and eventually produces an spontaneous action potential(arrhythmia). The dual role of CaMKII activation seems to be dependent on theduration of ischemia, being beneficial for the contractile recovery duringbrief ischemia, but detrimental for arrhythmias induction and when ischemia issevere enough for activating apoptosis/necrosis pathways. Elucidation of CaMKIIsignaling, assessing the participation of each CaMKII target, during I/R is ofparticular interest for using CaMKII inhibition as a potential therapeutic toolfor the treatment of arrhythmias and I/R injury.