Myocardial ischemic protection in natural mammalian hibernation

Abstract

Hibernating myocardium is an important clinical syndrome protecting the heart with chronic myocardial ischemia, named for its assumed resemblance to hibernating mammals in winter. However, the effects of myocardial ischemic protection have never been studied in true mammalian hibernation, which is a unique strategy for surviving extreme winter environmental stress. The goal of this investigation was to test the hypothesis that ischemic stress may also be protected in woodchucks as they hibernate in winter. Myocardial infarction was induced by coronary occlusion followed by reperfusion in naturally hibernating woodchucks in winter with and without hibernation and in summer, when not hibernating. The ischemic area at risk was similar among groups. Myocardial infarction was significantly less in woodchucks in winter, whether hibernating or not, compared with summer, and was similar to that resulting after ischemic preconditioning. Whereas several genes were up or downregulated in both hibernating woodchuck and with ischemic preconditioning, one mechanism was unique to hibernation, i.e., activation of cAMP-response element binding protein (CREB). When CREB was upregulated in summer, it induced protection similar to that observed in the woodchuck heart in winter. The cardioprotection in hibernation was also mediated by endothelial nitric oxide synthase, rather than inducible nitric oxide synthase. Thus, the hibernating woodchuck heart is a novel model to study cardioprotection for two major reasons: (1) powerful cardioprotection occurs naturally in winter months in the absence of any preconditioning stimuli, and (2) it resembles ischemic preconditioning, but with novel mechanisms, making this model potentially useful for clinical translation.

Molecular cloning, characterization and expression analysis of TGF-β and receptor genes in the woodchuck model

“…Chronic WHV infection in woodchucks usually leads to the development of HCC within the first 2-4 years of life, which makes woodchuck a natural model of human hepatocellular carcinoma with similar pathology and natural history (53,54). The woodchuck has also been used as a biomedical model for studies of obesity and energy balance, endocrine and metabolic function (55), cardiovascular (56), and cerebrovascular disease (57). Therefore, our work possesses the potential value for characterizing TGF-β family in these diseases by using woodchucks as animal models for corresponding studies.…”

Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck)

“…Woodchuck, the largest true hibernator, has been used in our laboratory for cardiac-protection studies (13). One of our projects was designed to evaluate remodeling changes in woodchuck hearts subjected to permanent (2 mo) coronary occlusion (and subsequent myocardial infarction).…”

“…A recent study from our group has demonstrated that the hibernating woodchuck heart is a novel model for studying cardioprotection because it resembles ischemic preconditioning in the absence of any preconditioning stimuli (13). However, the potential antiarrhythmic property has not been studied in this valuable animal model.…”

Lipid emulsion enhances cardiac performance after ischemia–reperfusion in isolated hearts from summer-active arctic ground squirrels

“…During hibernation, regulatory mechanisms depress metabolism to as low as 2% of basal rates for days to weeks to support cell preservation and long-term viability in a fasting state (Heldmaier et al 2004). Hibernating mammals have also been found to exhibit an extraordinary resistance to IR injury in numerous organs (Lindell et al 2005; Kurtz et al 2006; Dave et al 2006; Dave et al 2009; Bogren et al 2014; Yan et al 2015). …”