Cardiac adaptation and cardioprotection against arrhythmias and ischemia-reperfusion injury in mammalian hibernators

Abstract

Hibernation allows animals to enter an energy conserving state to survive severe drops in external temperatures and a shortage of food. It has been observed that the hearts of mammalian hibernators exhibit intrinsic protection against ischemia-reperfusion (I/R) injury and cardiac arrhythmias in the winter whether they are hibernating or not. However, the molecular and ionic mechanisms for cardioprotection in mammalian hibernators remain elusive. Recent studies in woodchucks (Marmota monax) have suggested that cardiac adaptation occurs at different levels and mediates an intrinsic cardioprotection prior to/in the winter. The molecular/cellular remodeling in the winter (with or without hibernation) includes (1) an upregulation of transcriptional factor, anti-apoptotic factor, nitric oxide synthase, protein kinase C-ε, and phosphatidylinositol-4,5-bisphosphate 3-kinase; (2) an upregulation of antioxidant enzymes (e.g. superoxide dismutase and catalase); (3) a reduction in the oxidation level of Ca2+/calmodulin-dependent protein kinase II (CaMKII); and (4) alterations in the expression and activity of multiple ion channels/transporters. Therefore, the cardioprotection against I/R injury in the winter is most likely mediated by enhancement in signaling pathways that are shared by preconditioning, reduced cell apoptosis, and increased detoxification of reactive oxygen species (ROS). The resistance to cardiac arrhythmias and sudden cardiac death in the winter is closely associated with an upregulation of the antioxidant catalase and a downregulation of CaMKII activation. This remodeling of the heart is associated with a reduction in the incidence of afterdepolarizations and triggered activities. In this short review article, we will discuss the seasonal changes in gene and protein expression profiles as well as alterations in the function of key proteins that are associated with the occurrence of cardioprotection against myocardial damage from ischemic events and fatal arrhythmias in a mammalian hibernator. Understanding the intrinsic cardiac adaptive mechanisms that confer cardioprotection in hibernators may offer new strategies to protect non-hibernating animals, especially humans, from I/R injury and ischemia-induced fatal cardiac arrhythmias.