Ischemic preconditioning: emerging evidence, controversy, and translational trials.

Protection against ischemia by ischemic preconditioning (IP) is seen in many tissues and organs. However, the preconditioning ischemia must precede lethal ischemia for this effect to occur, and the creation of ischemia to treat heart disease does not seem to be a realistic strategy. Accordingly, the underlying mechanisms that confer cardioprotection should be identified. Early studies revealed that IP causes two windows of cardioprotection, and subsequent efforts to detect cardioprotective factors have identified various triggers, mediators, and potent effectors of IP, such as endogenous receptor agonists (adenosine, catecholamines, bradykinin, and opioids), intracellular messengers [protein kinase C (PKC), p38MAPK, PI-3K, and PKA], ion channels such as KATP channels, enzymes including heat shock proteins (HSPs), superoxide dismutase (SOD), and 5'-nucleotidase, and other factors [nitric oxide (NO), growth factors, free radicals, and products of the arachidonic acid cascade]. Some of these factors are involved in several different pathways and may have multiple roles in IP-induced cardioprotection. Recently, however, certain problems have arisen such as controversies related to increasing knowledge and the relative lack of clinical studies in contrast to the intensive performance of basic studies. To overcome these problems, the latest studies have followed three major trends: (1) investigation of mechanisms to explain the current controversies, (2) detection of other unknown potent mechanisms, and (3) promotion of clinical trials based on the evidence from experimental studies in larger animals. Here, we summarize recent investigations on IP, emphasizing on the controversial issues and emerging factors, and discuss current research on the prevention or treatment of ischemic heart disease including some relevant clinical studies.