Original article Unraveling the mysteries of classical preconditioning James M. Downey a, *, Michael V. Cohen a,b a Department of Physiology, MSB 3074, College of Medicine, University of South Alabama, Mobile, AL 36688, USA b Department of Medicine, University of South Alabama, Mobile, AL, USA Received 15 June 2005; received in revised form 7 July 2005; accepted 19 July 2005 Available online 29 September 2005 Abstract Nearly two decades have passed since the first report about ischemic preconditioning.Although we do not yet know unequivocally what the final effector is, we have learned a lot about the signal transduction pathways that result in protection, and have some good prospects for the final step that results in survival or necrosis of the ischemic myocardium. Many investigators have contributed to our current knowledge. We were heartened to learn that four of our JMCC publications are included in the 20 top-cited papers in the journal’s history. It is gratifying that our prior publications have generated some interest and stimulated important debate as documented by the high number of citations by scientists in the bibliographies of their own papers. In this document, we have been asked to reflect on those four papers and comment on where they have led us. © 2005 Elsevier Ltd. All rights reserved. Keywords: Free radicals; Cardioprotection; Preconditioning; Protein kinase C; p38 MAP kinase; Tyrosine kinase As we celebrate this 25th anniversary year we were pleased to be informed that four of our manuscripts published in the Journal of Molecular and Cellular Cardiology have enjoyed particularly heavy citation activity. Since these papers were all published 6–8 years ago, it is interesting to reflect back on these studies today to see where (if anywhere) they have led. Our overall goal has been and continues to be to understand how the heart can be protected from the lethality of ischemia/reperfusion. That quest has been hampered because we do not understand the exact mechanism whereby ischemic tissue is killed in this process. The real breakthrough came when Murry et al. [1] discovered ischemic preconditioning. The value of that study was twofold. First, it revealed that cardioprotection was possible. Up to that point it had not been known whether anything could be done to modify the thresh- old for cell death in the ischemic heart. Secondly, and more importantly, it gave us a positive control to study. Any inves- tigator could produce cardioprotection in his or her labora- tory. All that was left was to unravel the puzzle and figure out just how preconditioning did its magic. Nobody in 1986 could envision that nature would be so reluctant to give up the secret of preconditioning. Neverthe- less the past 20 years have been met with significant progress in this area and we can not help but believe that we are now on the cusp of a clear understanding of the phenomenon. In its simplest form classical (also known as early) ischemic pre- conditioning is triggered by receptor occupancy that initiates a complex series of signal transduction pathways which put the heart into a preconditioned state. When the precondi- tioned heart is reperfused it executes a program involving acti- vation of key kinases which results in attenuation of oxygen radical production and modification of mitochondria such that they resist permeability transition pore opening. This sal- vages that population of myocytes that would have experi- enced death due to mitochondrial failure from transition pore opening. Of course there are a myriad of details left unan- swered, but the bare bones of the process are probably as described above. So how did we get here from there? For the most part the discoveries have to be chalked up to good detective work by the large number of investigators who have contributed to this effort. But there is no doubt that a number of lucky breaks helped to pave the road. For example, we were fortunate enough to first observe that preconditioning is triggered by receptor occupancy. We found that entrance into the precon- ditioned state is triggered by binding of adenosine receptors during the preconditioning ischemia [2]. That study was done * Corresponding author. Tel.: +1 251 460 6818; fax: +1 251 460 6464. E-mail address: jdowney@usouthal.edu (J.M. Downey). Journal of Molecular and Cellular Cardiology 39 (2005) 845–848 www.elsevier.com/locate/yjmcc 0022-2828/$ - see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2005.07.016