Background Emerging evidence suggests that ‘adaptive’ induction of autophagy (the cellular process responsible for the degradation and recycling of proteins and organelles) may confer a cardioprotective phenotype and represent a novel strategy to limit ischemia-reperfusion injury. Our aim was to test this paradigm in a clinically relevant, large animal model of acute myocardial infarction. Methods and Results Anesthetized pigs underwent 45 min of coronary artery occlusion and 3 hours of reperfusion. In the first component of the study, pigs received chloramphenicol succinate (CAPS: an agent that purportedly up-regulates autophagy; 20 mg/kg) or saline at 10 min before ischemia. Infarct size was delineated by tetrazolium staining and expressed as a % of the at-risk myocardium. In separate animals, myocardial samples were harvested at baseline and 10 min following CAPS treatment and assayed (by immunoblotting) for two proteins involved in autophagomsome formation: Beclin-1 and light chain (LC) 3B-II. To investigate whether the efficacy of CAPS was maintained with ‘delayed’ treatment, additional pigs received CAPS (20 mg/kg) at 30 min post-occlusion. Expression of Beclin-1 and LC3B-II, as well as infarct size, were assessed at end-reperfusion. CAPS was cardioprotective: infarct size was 25±5% and 41±4% in the CAPS-pretreated and CAPS-delayed treatment groups versus 56±5% in saline-controls (p<0.01 and p<0.05 versus control). Moreover, administration of CAPS was associated with increased expression of both proteins. Conclusion Our results demonstrate attenuation of ischemia-reperfusion injury with CAPS, and are consistent with the concept that induction of autophagy may provide a novel strategy to confer cardioprotection.

Autophagy is the tightly orchestrated cellular 'housekeeping' process responsible for the degradation and disposal of damaged and dysfunctional organelles and protein aggregates. In addition to its established basal role in the maintenance of normal cellular phenotype and function, there is growing interest in the concept that targeted modulation of autophagy under conditions of stress (most notably, ischaemia/reperfusion) may represent an adaptive mechanism and render the myocardium resistant to ischaemia/reperfusion injury. Our aims in this review are to: (i) provide a balanced overview of the emerging hypothesis that perturbation of autophagy may serve as a novel, intriguing, and powerful cardioprotective treatment strategy and (ii) summarize the controversies and challenges in exploiting autophagy as a therapeutic target for ischaemia/reperfusion injury.

Mechanical forces have a major influence on cell migration and are predicted to significantly impact cancer metastasis, yet this idea is currently poorly defined. In this study we have asked if changes in traction stress and migratory properties correlate with the metastatic progression of tumor cells. For this purpose, four murine breast cancer cell lines derived from the same primary tumor, but possessing increasing metastatic capacity, were tested for adhesion strength, traction stress, focal adhesion organization and for differential migration rates in two-dimensional and three-dimensional environments. Using traction force microscopy (TFM), we were surprised to find an inverse relationship between traction stress and metastatic capacity, such that force production decreased as the metastatic capacity increased. Consistent with this observation, adhesion strength exhibited an identical profile to the traction data. A count of adhesions indicated a general reduction in the number as metastatic capacity increased but no difference in the maturation as determined by the ratio of nascent to mature adhesions. These changes correlated well with a reduction in active beta-1 integrin with increasing metastatic ability. Finally, in two dimensions, wound healing, migration and persistence were relatively low in the entire panel, maintaining a downward trend with increasing metastatic capacity. Why metastatic cells would migrate so poorly prompted us to ask if the loss of adhesive parameters in the most metastatic cells indicated a switch to a less adhesive mode of migration that would only be detected in a three-dimensional environment. Indeed, in three-dimensional migration assays, the most metastatic cells now showed the greatest linear speed. We conclude that traction stress, adhesion strength and rate of migration do indeed change as tumor cells progress in metastatic capacity and do so in a dimension-sensitive manner.

Reperfusion is the definitive treatment to reduce infarct size and other manifestations of postischemic injury. However, reperfusion contributes to postischemic injury, and, therefore, reperfusion therapies do not achieve the optimal salvage of myocardium. Other tissues as well undergo injury after reperfusion, notably, the coronary vascular endothelium. Postconditioning has been shown to have salubrious effects on different tissue types within the heart (cardiomyocytes, endothelium) and to protect against various pathologic processes, including necrosis, apoptosis, contractile dysfunction, arrhythmias, and microvascular injury or "no-reflow." The mechanisms by which postconditioning alters the pathophysiology of reperfusion injury is exceedingly complex and involves physiological mechanisms (e.g., delaying re-alkalinization of tissue pH, triggering release of autacoids, and opening and closing of various channels) and molecular mechanisms (activation of kinases) that affect cellular and subcellular targets or effectors. The physiologic responses to postconditioning are not isolated or mutually exclusive, but are interactive, with one response affecting another in an integrated manner. This integrated response on multiple targets differs from the monotherapy approach by drugs that have failed to reduce reperfusion injury on a consistent basis and may underlie the efficacy of this therapeutic approach across species and in human trials.

Autophagy is the endogenous, tightly regulated cellular "housekeeping" process responsible for the degradation of damaged and dysfunctional cellular organelles and protein aggregates. There is a growing consensus that autophagy is upregulated in the setting of myocardial ischemia-reperfusion. Moreover, emerging data suggest that autophagy may serve as an adaptive process and confer increased resistance to ischemia-reperfusion injury. Our aims in this review are to (1) provide a brief synopsis of process of autophagy (including an overview of the key molecular mediators of this catabolic process and its relationship with other cardiac signaling pathways) and (2) most importantly, summarize the current evidence for versus against the intriguing concept of autophagy-mediated cardioprotection.