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. 2013 May 15;8(5):e62948.
doi: 10.1371/journal.pone.0062948. Print 2013.

The bitter fate of the sweet heart: impairment of iron homeostasis in diabetic heart leads to failure in myocardial protection by preconditioning

Vladimir Vinokur  1 , Eduard Berenshtein, Baruch Bulvik, Leonid Grinberg, Ron Eliashar, Mordechai Chevion
Affiliations

The bitter fate of the sweet heart: impairment of iron homeostasis in diabetic heart leads to failure in myocardial protection by preconditioning

Vladimir Vinokur et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. The 3 basic experimental protocols.
(i) continuous perfusion (lower bar), (ii) ischemia/reperfusion (I/R) (middle bar) and (iii) ischemic pre-conditioning (IPC) followed by I/R (upper bar).
Figure 2
Figure 2. Ferritin levels (Panels A and B) and ferritin saturation with iron (Panels C and D) in hearts of non-diabetic and STZ-diabetic rats.
Under I/R protocol (□), the hearts were stabilized for 25 min followed by global ischemia (35 min) and reperfusion (60 min). Under IPC+I/R protocol (•), the stabilization phase (10 min) was followed by the IPC procedure (15 min of intermittent ischemia (2 min) followed by perfusion (3 min)), prolonged ischemia and reperfusion. The perfusion protocol (▴) was run to detect spontaneous changes in Ft during the entire protocol of 120 min. Mean±SEM are shown. # denotes p<0.001 versus the values for either I/R or Perfusion; * denotes p<0.01 versus either I/R or Perfusion; ^ denotes p<0.05 versus either I/R or Perfusion.
Figure 3
Figure 3. Ferritin (Ft) levels in hearts from STZ-induced diabetic rats subjected to ischemic preconditioning followed by prolonged ischemia and reperfusion (IPC+I/R protocol) when treated with a cocktail of proteases inhibitors.
Mean±SEM are shown. * - denotes p<0.01 versus the mean value at 10 min. # - denotes p<0.05 versus the treated group at the same time point along the protocol.
See this image and copyright information in PMC

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Publication types

Grants and funding

This research was supported by funds from the Paulina and Dr. Moshe (Monek) Memorial fund, from the German-Israel Foundation for Scientific Research and Development (GIF 1061-59.2/2008) and from The Israel Science Foundation (ISF 489/12) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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