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Selenide Targets to Reperfusing Tissue and Protects It From Injury*

Iwata, Akiko PhD1; Morrison, Michael L. PhD1; Blackwood, Jennifer E. MPH2; Roth, Mark B. PhD1

doi: 10.1097/CCM.0000000000000971
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Objectives: Since blood selenium levels decrease after ischemia and reperfusion injury, and low blood selenium correlates with negative outcome, we designed and performed experiments to determine how selenium distribution is affected by ischemia reperfusion injury. Furthermore, we tested whether different chemical forms of selenium would affect outcome after ischemia and reperfusion injury. We also examined the metabolic effects of selenide administration.

Design: Laboratory investigation.

Setting: Animal research laboratory.

Subjects: Adult male C57BL/6 mice.

Interventions: To determine selenium localization, we administered tracer doses of radioactive selenium 75 in the form of selenite or selenide and measured blood and tissue selenium levels after ischemia and reperfusion injury. Anesthetized mice were subjected to myocardial ischemia reperfusion injury (coronary artery occlusion for 60 min followed by 5 min of reperfusion after occlusion was removed) or hindlimb ischemia reperfusion injury (left leg tourniquet for 90 min followed by 5 min reperfusion after tourniquet removal). To determine whether exogenous selenium administration could reduce ischemia reperfusion injury, we synthesized and administered sodium hydroselenide and sodium selenite solutions (0.05–2.4 mg/kg). Solutions were administered at the end of coronary artery occlusion but before reperfusion. In order to determine the metabolic effects of selenide administration, we exposed mice to hydrogen selenide gas (0–5 ppm) mixed into air (20.95% oxygen) for up to 3 hours.

Measurements and Main Results: In targeting assays, we measured blood and tissue selenium levels. We observed that blood selenium decreases after myocardial ischemia reperfusion and displays an inverse correlation with injury severity; selenium accumulation in heart correlates directly with injury severity. We also measured whether oxidized selenium, selenite, and reduced selenium, selenide, would target to injured heart tissue in myocardial ischemia reperfusion and injured leg muscle in a hindlimb model of ischemia reperfusion. Only selenide targets to injured tissue. We also measured damage after myocardial ischemia reperfusion injury using morphometry, neutrophil accumulation, blood cardiac troponin levels, and echocardiography and observed in all assays that selenide reduced damage to the heart; selenite was not effective. And finally, to assay metabolism, we measured oxygen consumption, carbon dioxide production, and body core temperature before, during, and after hydrogen selenide administration. All measurements indicate that selenide decreases metabolism.

Conclusions: Selenide targets to reperfusing tissue and reduces reperfusion injury perhaps by affecting oxygen metabolism.

1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

2Emergency Medical Services, Seattle and King County Public Health, Seattle, WA.

* See also p. 1528.

Drs. Iwata, Morrisonm, and Roth received support for article research from Defense Advanced Research Projects Agency (DARPA). Their institution received grant support from DARPA. Dr. Blackwood disclosed that she does not have any potential conflicts of interest.

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