Abstract
Ischemic preconditioning (IPC) inhibits Ca2+‐loading during ischemia which contributes to cardioprotection by inhibiting mechanical injury due to hypercontracture and biochemical injury through mitochondrial permeability transition (MPT) pores during reperfusion. However, whether remote‐IPC reduced Ca2+‐loading during ischemia and its subsequent involvement in inhibiting MPT pore formation during reperfusion has not been directly shown. We have developed a cellular model of remote IPC to look at the impact of remote conditioning on Ca2+‐regulation and MPT pore opening during simulated ischemia and reperfusion, using fluorescence microscopy. Ventricular cardiomyocytes were isolated from control rat hearts, hearts preconditioned with three cycles of ischemia/reperfusion or naïve myocytes remotely conditioned with effluent collected from preconditioned hearts. Both conventional‐IPC and remote‐IPC reduced the loss of Ca2+‐homeostasis and contractile function following reenergization of metabolically inhibited cells and protected myocytes against ischemia/reperfusion injury. However, only conventional‐IPC reduced the Ca2+‐loading during metabolic inhibition and this was independent of any change in sarcKATP channel activity but was associated with a reduction in Na+‐loading, reflecting a decrease in Na/H exchanger activity. Remote‐IPC delayed opening of the MPT pores in response to ROS, which was dependent on PKCε and NOS‐signaling. These data show that remote‐IPC inhibits MPT pore opening to a similar degree as conventional IPC, however, the contribution of MPT pore inhibition to protection against reperfusion injury is independent of Ca2+‐loading in remote IPC. We suggest that inhibition of the MPT pore and not Ca2+‐loading is the common link in cardioprotection between conventional and remote IPC.
Highlights
Reperfusion of ischemic myocardium induces substantial cellular injury resulting from mechanical and biochemical necrotic injury (Honda et al 1047; Piper et al 2004; Halestrap 2006), which involves substantial Ca2+-loading during ischemia, driven by the “coupled exchanger” mechanism between the sodium/hydrogen exchanger (NHE) and sodium/calcium exchanger (NCX) (Tani and Neely 1989; Allen and Xiao 2003)
We looked at the ability of “conditioned perfusate” collected as the effluent from intact hearts subject to three cycles of Ischemic preconditioning (IPC), to remotely condition and protect “na€ıve” myocytes against ischemia/ reperfusion injury
We have previously shown that ischemic preconditioning of the intact rat heart confers a cardioprotective phenotype to the isolated single ventricular myocytes, and this protection mirrors that seen in the intact heart, which may be linked to a decrease in Ca2+-loading (Rodrigo and Samani 2008)
Summary
Reperfusion of ischemic myocardium induces substantial cellular injury resulting from mechanical and biochemical necrotic injury (Honda et al 1047; Piper et al 2004; Halestrap 2006), which involves substantial Ca2+-loading during ischemia, driven by the “coupled exchanger” mechanism between the sodium/hydrogen exchanger (NHE) and sodium/calcium exchanger (NCX) (Tani and Neely 1989; Allen and Xiao 2003). The mitochondria become reenergized and the membrane potential repolarizes, leading to the production of ATP and ROS (Rodrigo and Standen 2005a; Garcia-Dorado et al 2012) This combines with the high [Ca2+]i to trigger large SR-driven Ca2+-oscillations resulting in strong hypercontracture inducing mechanical injury (Inserte et al 2002; Kevin et al 2003; Piper et al 2004; Rodrigo and Standen 2005a) and opening of the mitochondrial permeability transition (MPT) pore resulting in biochemical driven necrosis (Griffiths and Halestrap 1995; Hausenloy et al 2004).
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