Abstract
Whether the diabetic heart benefits from ischemic preconditioning (IPC), similar to the non-diabetic heart, is a subject of controversy. We recently proposed new roles for iron and ferritin in IPC-protection in Type 1-like streptozotocin-induced diabetic rat heart. Here, we investigated iron homeostasis in Cohen diabetic sensitive rat (CDs) that develop hyperglycemia when fed on a high-sucrose/low-copper diet (HSD), but maintain normoglycemia on regular-diet (RD). Control Cohen-resistant rats (CDr) maintain normoglycemia on either diet. The IPC procedure improved the post-ischemic recovery of normoglycemic hearts (CDr-RD, CDr-HSD and CDs-RD). CDs-HSD hearts failed to show IPC-associated protection. The recovery of these CDs-HSD hearts following I/R (without prior IPC) was better than their RD controls. During IPC ferritin levels increased in normoglycemic hearts, and its level was maintained nearly constant during the subsequent prolonged ischemia, but decayed to its baseline level during the reperfusion phase. In CDs-HSD hearts the baseline levels of ferritin and ferritin-saturation with iron were notably higher than in the controls, and remained unchanged during the entire experiment. This unique and abnormal pattern of post-ischemic recovery of CDs-HSD hearts is associated with marked changes in myocardial iron homeostasis, and suggests that iron and iron-proteins play a causative role/s in the etiology of diabetes-associated cardiovascular disorders.
Highlights
Cardiac ailments constitute leading causes of morbidity and mortality in Western world [1,2]
In this study we investigated the physiology and iron homeostasis in hearts of genetically modified and diabetic-prone Cohen rats
Cohen rats develop diet-induced Type 2-like diabetes when fed on high-sucrose and low-copper diet (CDs-high-sucrose/low-copper diet (HSD))
Summary
Cardiac ailments constitute leading causes of morbidity and mortality in Western world [1,2]. We have recently demonstrated [8,9,10] that cardiac IPC initiates marked de novo synthesis of ferritin, which in turn, serves as a 'sink' for high levels of ischemia-induced released iron ions, protecting the heart against iron-mediated I/R damage. We have shown, that ferritin level in naïve (non-manipulated) hearts from Type-1-like streptozotocin (STZ)induced diabetic rats was 2-fold higher than in non-diabetic controls [8]. This was in accord with the enhanced resistance of the diabetic heart to I/R injury when compared to controls. A number of proteins, like hephaestin and ceruloplasmin, are involved in cellular uptake and secretion of iron These proteins contain essential copper ions in their active center or their prosthetic group. A copper-deficient diet may prove detrimental for the maintenance of adequate iron homeostasis, on the cellular and whole organism levels, leading to a variety of disorders [13]
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