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Heme arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects.

ABSTRACT: Heme arginate can induce heme oxygenase-1 to protect tissue against ischemia-reperfusion injury. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging measures changes in tissue oxygenation with a high spatial and temporal resolution. BOLD imaging was applied to test the effect of heme arginate on experimental ischemia reperfusion injury in the calf muscles.A two period, controlled, observer blinded, crossover trial was performed in 12 healthy male subjects. Heme arginate (1?mg/kg body weight) or placebo were infused 24 h prior to a 20 min leg ischemia induced by a thigh cuff. 3 Tesla BOLD-imaging of the calf was performed and signal time courses from soleus, gastrocnemius and tibialis anterior muscle were available from 11 participants for technical reasons.Peak reactive hyperemia signal of the musculature was significantly increased and occurred earlier after heme arginate compared to placebo (106.2 ± 0.6% at 175 ± 16s vs. 104.5 ± 0.6% at 221 ± 19s; p?=?0.025 for peak reperfusion and p?=?0.012 for time to peak).A single high dose of heme arginate improves reperfusion patterns during ischemia reperfusion injury in humans. BOLD sensitive, functional MRI is applicable for the assessment of experimental ischemia reperfusion injury in skeletal muscle.

SUBMITTER: Andreas M

PROVIDER: S-EPMC3438022 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Heme arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects.

Andreas Martin M Schmid Albrecht Ingo AI Doberer Daniel D Schewzow Kiril K Weisshaar Stefan S Heinze Georg G Bilban Martin M Moser Ewald E Wolzt Michael M

Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance 20120802

<h4>Unlabelled</h4><h4>Background</h4>Heme arginate can induce heme oxygenase-1 to protect tissue against ischemia-reperfusion injury. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging measures changes in tissue oxygenation with a high spatial and temporal resolution. BOLD imaging was applied to test the effect of heme arginate on experimental ischemia reperfusion injury in the calf muscles.<h4>Methods</h4>A two period, controlled, observer blinded, crossover trial was pe ...[more]

PMID: 22857721

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Project description:Background: Ischemia reperfusion injury (IRI) plays a major role in solid organ transplantation. The length of warm ischemia time is critical for the extent of tissue damage in renal IRI. In this experimental study we hypothesized that local release of labile heme in renal tissue is triggered by the duration of warm ischemia (15 vs. 45 min IRI) and mediates complement activation, cytokine release, and inflammation. Methods: To induce IRI, renal pedicle clamping was performed in male C57BL/6 mice for short (15 min) or prolonged (45 min) time periods. Two and 24 h after experimental ischemia tissue injury labile heme levels in the kidney were determined with an apo-horseradish peroxidase assay. Moreover, renal injury, cytokines, and C5a and C3a receptor (C5aR, C3aR) expression were determined by histology, immunohistochemistry and qPCR, respectively. In addition, in vitro studies stimulating bone marrow-derived macrophages with LPS and the combination of LPS and heme were performed and cytokine expression was measured. Results: Inflammation and local tissue injury correlated with the duration of warm ischemia time. Labile heme concentrations in renal tissue were significantly higher after prolonged (45 min) as compared to short (15 min) IRI. Notably, expression of the inducible heme-degrading enzyme heme oxygenase-1 (HO-1) was up-regulated in kidneys after prolonged, but not after short IRI. C5aR, the pro-inflammatory cytokines IL-6 and TNF-α as well as pERK were up-regulated after prolonged, but not after short ischemia times. Consecutively, neutrophil infiltration and up-regulation of pro-fibrotic cytokines such as CTGF and PAI were more pronounced in prolonged IRI in comparison to short IRI. In vitro stimulation of macrophages with LPS revealed that IL-6 expression was enhanced in the presence of heme. Finally, administration of the heme scavenger human serum albumin (HSA) reduced the expression of pro-inflammatory cytokines, C3a receptor and improved tubular function indicated by enhanced alpha 1 microglobulin (A1M) absorption after IRI. Conclusions: Our data show that prolonged duration of warm ischemia time increased labile heme levels in the kidney, which correlates with IRI-dependent inflammation and up-regulation of anaphylatoxin receptor expression.

Dataset Information

Heme arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects.

Publications

Heme arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects.

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