Ischemic Preconditioning And Myocardial Infarction: An Update and Perspective

Abstract

Myocardial infarction is the leading cause of mortality in Western societies with annual expenditures of $431.8 billion spent on coronary artery disease in man. Therapeutics to combat infarction from myocardial injury, based on studies of ischemic preconditioning (IPC), are currently in progress. Hence, this review provides an update on IPC, including general and molecular mechanisms responsible for IPC and the effects of IPC in models of aging or disease. A summary of therapeutics shown to possess efficacy in preclinical and clinical trials and future directions of studies regarding cardiac IPC are also discussed.

Figure 1. Signaling components activated during IPC

Upon initiation of the IPC stimulus, endogenous triggers such as adenosine, opioids, and bradykinin are released. These endogenous agents bind to membrane receptors and when released in large enough quantities they achieve a threshold to activate intracellular signaling. Additional receptors, such as tyrosine kinase receptors (TKRs), may also be involved. Receptor activation results in receptor internalization via caveolin and βARK. This leads to the activation of multiple cellular pathways, including arachidonic acid metabolites (AA), ion channels, such as sK_ATP and connexin 43 (Cx43), JAK/STAT, MAPK, tyrosine kinases such as Src and Lck, Bcl-2 family members such as Bcl-2 and Bax, and the PI3k pathway. The PI3k pathway is known to regulate PKCε, MDM2/p53, Akt, GSK3β, eNOS and the MPTP. Activation of these components leads to modulation of mitochondrial components such as Cx43, MPTP, mK_ATP and the electron transport chain (ETC), which modulate production of reactive oxygen species (ROS). Those components which are activated by IPC are represented by circles while the agents inactivated by IPC are in rectangles.