Abstract
Cardiovascular dysfunction is a major complication of diabetes. Examining mechanistic aspects underlying the incapacity of the diabetic heart to respond to ischemic preconditioning (IPC), we could show that the alterations in iron homeostasis can explain this phenomenon. Correlating the hemodynamic parameters with levels of ferritin, the main iron storage and detoxifying protein, without and with inhibitors of protein degradation, substantiated this explanation. Diabetic hearts were less sensitive to ischemia-reperfusion stress, as indicated by functional parameters and histology. Mechanistically, since ferritin has been shown to provide cellular protection against insults, including ischemia-reperfusion stress and as the basal ferritin level in diabetic heart was 2-fold higher than in controls, these are in accord with the greater resistance of the diabetic heart to ischemia-reperfusion. Additionally, during ischemia-reperfusion, preceded by IPC, a rapid and extensive loss in ferritin levels, during the prolonged ischemia, in diabetic heart but not in non-diabetic controls, provide additional substantiation to the explanation for loss of respond to IPC. Current research is shedding light on the mechanism behind ferritin degradation as well, suggesting a novel explanation for diabetes-induced loss of cardioprotection.
Highlights
Despite recent advancements in the prevention and treatment of heart disease, cardiac ailments continue to be a leading cause of mortality in the Western world [1]
Repeated episodes of myocardial ischemia and reperfusion may lead to preconditioning of the heart, allowing the myocardium to better withstand subsequent severe ischemia and to avoid, or at least reduce, the consequences of a myocardial infarction
We found that subjecting the diabetic heart to ischemic preconditioning (IPC) did not confer protection, and rendered the diabetic heart more sensitive to prolonged ischemia and reperfusion than without prior IPC
Summary
Despite recent advancements in the prevention and treatment of heart disease, cardiac ailments continue to be a leading cause of mortality in the Western world [1]. Amongst various techniques studied to protect the heart against the consequences of coronary stenosis and occlusion, IPC is considered to have therapeutic potential for reducing myocardial injury during cardiac surgery, percutaneous transluminal coronary angioplasty (PTCA) and heart transplantation [2,3]. Some publications have documented worse recovery of heart function following prolonged ischemia, in diabetic patients, as in diabetic animals, compared to non-diabetic hearts. Other published lines of evidence have clearly demonstrated the opposite - a significantly better recovery of the diabetic than the nondiabetic heart, after prolonged ischemia. The literature is not consistent with studies showing enhanced tolerance of diabetic hearts to prolonged ischemia and reperfusion-injury [4,5], while others contradict this finding [6]. The diabetic heart demonstrates a poor capacity to respond to IPC [8,9,10], in contrast to the non-diabetic heart, where IPC is highly protective
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