Cardioprotection is a fairly vague term which refers to the reduction of damage from myocardial ischemia/reperfusion by several endogenous phenomena, such as hibernation [23, 37], ischemic preconditioning [32, 41], ischemic postconditioning [20, 43], and remote conditioning [19, 22] as well as by pharmacological interventions. With the recognition of the postconditioning phenomenon [43], myocardial reperfusion injury has been appreciated as a reality [42] from which protection is clinically feasible [36, 38, 39]. The signal transduction of cardioprotection is under intense investigation, with the ultimate aim to identify targets for pharmacological recruitment of cardioprotection [21]; three major pathways have been characterized—the cGMP/PKG-pathway [11], the reperfusion injury salvage kinase (RISK)-pathway [18] and the survivor activating factor enhancement (SAFE)-pathway [31]. These three major pathways are not mutually exclusive, but potentially cooperative, and they are recruited by the above cardioprotective phenomena to a different extent. The cardioprotective signaling pathways are thought to converge on the mitochondria [21], and various mitochondrial proteins without or with channel structure have been identified as central elements in cardioprotection. Several signaling pathways of cardioprotection converge to inhibit glycogen synthase kinase-3b which in its phosphorylated state increases the threshold for mitochondrial permeability transition pore (MPTP) opening [25, 26].

The MPTP is a large-conductance megachannel which is traditionally thought to be formed by an arrangement of the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane, the adenine nucleotide transporter (ANT) in the inner membrane and cyclophilin D in the matrix [30]. The MPTP is either not present or mostly closed under physiological conditions, but opens in response to high concentrations of calcium. The calciuminduced opening of MPTP is favoured by high concentrations of inorganic phosphate, reactive oxygen species, and nitric oxide and a reduction of the inner membrane potential—all conditions which occur during myocardial ischemia and reperfusion; acidosis and magnesium ions inhibit/delay MPTP opening [8, 13, 29, 30, 40, 44]. In addition, pro-and anti-apoptotic members of the Bcl-family interact with the MPTP [3]. Formation and opening of the MPTP results in depolarization of the inner membrane potential and matrix swelling and ultimately in rupture of the outer membrane. Proteins, among them cytochrome C, are then released from the intermembrane space into the cytosol and activate caspase cascades to initiate cellular fragmentation and ultimately cell death. In 1993, both the groups of Crompton [12] and Halestrap [16] demonstrated that MPTP opened upon reperfusion following myocardial ischemia and that cyclosporine A protected from reperfusion injury. Cyclosporine A inhibits binding of cyclophilin D to ANT, thereby MPTP opening and ultimately cell death; ablation of the Ppif gene which encodes for cyclophilin D [4, 33] and cyclosporine A [4] therefore reduce infarct size resulting from myocardial ischemia and reperfusion. Yellon et al. first proposed that inhibition of MPTP opening could be the effector of ischemic preconditioning [17], and Ovize et al. shortly thereafter proposed MPTP inhibition as the effector of ischemic postconditioning [2];