Remote ischemic preconditioning of cardiomyocytes inhibits the mitochondrial permeability transition pore independently of reduced calcium‐loading or sarcKATP channel activation

• Published in: Physiological reports Vol. 2; no. 11
• Main Authors: Turrell, Helen E., Thaitirarot, Chokanan, Crumbie, Hayley, Rodrigo, Glenn
• Format: Journal Article
• Language: English
• Published: United States Wiley Periodicals, Inc 01-11-2014
• Subjects: Ca2+‐Loading; ischemic preconditioning; MPT pore; Original Research; remote ischemic preconditioning; sodium/hydrogen exchanger; remote ischemic preconditioning; ischemic preconditioning; MPT pore; Ca2+‐Loading; sodium/hydrogen exchanger
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.12231

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.
e12231
Remote ischemic preconditioning (IPC) provides a similar level of protection against ischemia–reperfusion injury to that of conventional‐IPC. This study shows that unlike conventional‐IPC, this was independent of any reduction in Na or Ca2+‐loading during the simulated ischemic event but results from a direct PKCε‐dependent inhibition of the mitochondrial permeability transition pore.