Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy

Higdon, Ashlee N.; Benavides, Gloria A.; Chacko, Balu K.; Ouyang, Xiaosen; Johnson, Michelle S.; Landar, Aimee; Zhang, Jianhua; Darley‐Usmar, Victor

doi:10.1152/ajpheart.00584.2011

Cited by 134 publications

(148 citation statements)

References 83 publications

(98 reference statements)

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“…Intriguingly, treatment with Hx or NAC preserves intracellular Ca 2+ handling and single cell contractility and thus further supports a model where direct heme/ROS-mediated effects on Ca 2+ handling proteins is the main cause of reduced cardiac function when Hx is depleted. Intriguingly, intracellular hemin can trigger oxidative modification of the mitochondrial outer membrane voltage-dependent anion channel (VDAC) [59], thus impairing mitochondrial Ca 2+ influx [60]. This has been uncovered in endothelial cells and a similar mechanism is likely to occur in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Ingoglia

Sag

Rex

et al. 2017

Free Radical Biology and Medicine

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Heart failure is a leading cause of morbidity and mortality in patients affected by different disorders associated to intravascular hemolysis. The leading factor is the presence of pathologic amount of pro-oxidant free heme in the bloodstream, due to the exhaustion of the natural heme scavenger Hemopexin (Hx). Here, we evaluated whether free heme directly affects cardiac function, and tested the therapeutic potential of replenishing serum Hx for increasing serum heme buffering capacity.The effect of heme on cardiac function was assessed in vitro, on primary cardiomyocytes and H9c2 myoblast cell line, and in vivo, in Hx -/-mice and in genetic and acquired mouse models of intravascular hemolysis. Purified Hx or anti-oxidants N-Acetyl-L-cysteine and α-tocopherol were used to counteract heme cardiotoxicity.In mice, Hx loss/depletion resulted in heme accumulation and enhanced reactive oxygen species (ROS) production in the heart, which ultimately led to severe systolic dysfunction. Similarly, high ROS reduced systolic Ca 2+ transient amplitudes and fractional shortening in primary cardiomyocytes exposed to free heme. In keeping with these Ca 2+ handling alterations, oxidation and CaMKIIdependent phosphorylation of Ryanodine Receptor 2 were higher in Hx -/-hearts than in controls.Administration of anti-oxidants prevented systolic failure both in vitro and in vivo. Intriguingly, Hx rescued contraction defects of heme-treated cardiomyocytes and preserved cardiac function in hemolytic mice.We show that heme-mediated oxidative stress perturbs cardiac Ca 2+ homeostasis and promotes contractile dysfunction. Scavenging heme, Hx counteracts cardiac heme toxicity and preserves left ventricular function. Our data generate the rationale to consider the therapeutic use of Hx to limit the cardiotoxicity of free heme in hemolytic disorders.

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Section: Discussionmentioning

confidence: 99%

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Ingoglia

Sag

Rex

et al. 2017

Free Radical Biology and Medicine

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“…Both oxidized lipids and hydrogen peroxide are known to damage mitochondria [14,22]. For example, mitochondrial dysfunction is a major consequence of lipid peroxidation, promoted by haeme and haeme proteins and is characterized by irreversible permeabilization of the mitochondrial membrane, a decrease in membrane potential, loss of cellular bioenergetics and mitochondrial swelling [24][25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

“…PO-PCF caused a dramatic increase in oxidative stress in cardiomyocytes as determined by DCF fluorescence assay ( Figure 4A) compared with the plasma control from the same patient. Mitochondria are one of the most sensitive targets of ROS and several studies demonstrate mitochondrial dysfunction via oxidation of mitochondrial proteins, inhibition of membrane potential and damage to the organelle [14,21,22]. In vitro PO-PCF treatment of cardiomyocytes also caused a decrease in mitochondrial membrane potential as determined by the poor dimerisation of JC-1 in the mitochondria (Figures 4B and 4D).…”

Section: Po-pcf Induces Oxidative Stress and Mitochondrial Damage Inmentioning

confidence: 90%

Decreased Bioenergetic Health Index in monocytes isolated from the pericardial fluid and blood of post-operative cardiac surgery patients

et al. 2015

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SynopsisMonitoring the bioenergetics of leucocytes is now emerging as an important approach in translational research to detect mitochondrial dysfunction in blood or other patient samples. Using the mitochondrial stress test, which involves the sequential addition of mitochondrial inhibitors to adherent leucocytes, we have calculated a single value, the Bioenergetic Health Index (BHI), which represents the mitochondrial function in cells isolated from patients. In the present report, we assess the BHI of monocytes isolated from the post-operative blood and post-operative pericardial fluid (PO-PCF) from patients undergoing cardiac surgery. Analysis of the bioenergetics of monocytes isolated from patients' PO-PCF revealed a profound decrease in mitochondrial function compared with monocytes isolated from their blood or from healthy controls. Further, patient blood monocytes showed no significant difference in the individual energetic parameters from the mitochondrial stress test but, when integrated into the BHI evaluation, there was a significant decrease in BHI compared with healthy control monocytes. These data support the utility of BHI measurements in integrating the individual parameters from the mitochondrial stress test into a single value. Supporting our previous finding that the PO-PCF is pro-oxidant, we found that exposure of rat cardiomyocytes to PO-PCF caused a significant loss of mitochondrial membrane potential and increased reactive oxygen species (ROS). These findings support the hypothesis that integrated measures of bioenergetic health could have prognostic and diagnostic value in translational bioenergetics.

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“…However, mitochondrial bioenergetic analyses have not been explored extensively in the context of Hb cytotoxicity. Recently, however, heme and cell-free Hb have been shown to disrupt mitochondrial bioenergetic function in different cell types (22)(23)(24). Using lung epithelial cells (E10) as an AT1 cell model, we investigated the differential toxicity of acellular Hb and its oxidized species on the mitochondrial transmembrane potential and also on oxygen consumption rate (OCR).…”

Section: Clinical Relevancementioning

confidence: 99%

“…The dye preferentially accumulates in the mitochondria, as indicated by the high 590:530 nm emission fluorescence ratio. The ratio decreases drastically with a loss of mitochondrial bioenergetic function (23). We monitored the changes in the red: green ratio and expressed them on a percent scale drawn from the ratio obtained from oligomycin (100% hyperpolarized cells) and from FCCP (0% or completely depolarized cells).…”

Section: Effect Of Oxidized Hb Exposure On E10 Cellsmentioning

confidence: 99%

Oxidized Ferric and Ferryl Forms of Hemoglobin Trigger Mitochondrial Dysfunction and Injury in Alveolar Type I Cells

Chintagari

Jana

Alayash

2016

Am J Respir Cell Mol Biol

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Lung alveoli are lined by alveolar type (AT) 1 cells and cuboidal AT2 cells. The AT1 cells are likely to be exposed to cell-free hemoglobin (Hb) in multiple lung diseases; however, the role of Hb redox (reduction-oxidation) reactions and their precise contributions to AT1 cell injury are not well understood. were reversed by the addition of scavenger proteins, haptoglobin and hemopexin. Collectively, these data establish, for the first time, a central role for cell-free Hb in lung epithelial injury, and that these effects are mediated through the redox transition of Hb to higher oxidation states.

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Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy

Abstract: Darley-Usmar VM. Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy.

Cited by 134 publications

References 83 publications

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

Decreased Bioenergetic Health Index in monocytes isolated from the pericardial fluid and blood of post-operative cardiac surgery patients

Oxidized Ferric and Ferryl Forms of Hemoglobin Trigger Mitochondrial Dysfunction and Injury in Alveolar Type I Cells

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