Cardiomyocyte Death Induced by Myocardial Ischemia and Reperfusion

Dumont, Ewald A. W. J.; Hofstra, Leo; Heerde, Waander L. van; Eijnde, Stephan van den; Doevendans, Pieter A.; deMuinck, Ebo D.; Daemen, M.A.R.C.; Smits, J. F. M.; Frederik, Peter M.; Wellens, Hein J.J.; Daemen, M. J. A. P.; Reutelingsperger, Chris

doi:10.1161/01.cir.102.13.1564

Cited by 149 publications

(48 citation statements)

References 24 publications

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“…High concentrations of ROS/H 2 O 2 induce PARP activation and [ATP] i /NAD þ depletion, leading to cardiac necrosis, and the use of PARP À/À mice or PARP inhibitors reduces the infarct area (necrosis) by B20-25%, [13][14][15] indicating that other mechanisms may be involved (see below). EM analysis shows that the infarct area exhibits both necrotic and apoptotic changes, 17,18 which are very similar to those seen in the present study (Figure 5Hb). The present study showed that PARP inhibitors completely inhibited the caspase 3-independent necrotic changes ( Figure 3g), but had only a small protective effect (B15-20%, Figure 5F and Giii) on the caspase 3-dependent nuclear changes.…”

Section: Discussionsupporting

confidence: 88%

“…[17][18][19] To our knowledge, this is the first report describing the molecular mechanisms involved in the two sets of death features in the same cell.…”

Section: Discussionmentioning

confidence: 88%

“…These ultrastructure changes were very similar to those seen in the infarct/peri-infarct zone in I/R animal studies. [16][17][18] It has been suggested that PTP opening induces water influx, resulting in disruption of the outer mitochondrial membrane (OMM, i.e. hernia), followed by cytC release.…”

Section: Inhibition Of Both Trpm2 Opening and Parp Activation Preventmentioning

confidence: 99%

“…[13][14][15] Electron microscopy (EM) shows that I/R-induced cell death does not result in a classic apoptotic or necrotic morphology, but in the appearance of both sets of characteristics in a single myocyte. [16][17][18] The ultrastructure changes include EM-TdT-mediated dUTP-X nick end labeling (TU-NEL)-positive nuclear fragmentation, plasma membrane permeabilization, and mitochondrial hernia with loss of cristae. This untypical mode of cell death is not restricted to cardiac cells, as it is also seen by EM in the rat brain cortex after cerebral artery occlusion.…”

Section: Introductionmentioning

confidence: 99%

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Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

et al. 2005

Cell Death Differ

106

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Overproduction of reactive oxygen species is one of the major causes of cell death in ischemic-reperfusion (I/R) injury. In I/R animal models, electron microscopy (EM) has shown mixed apoptotic and necrotic characteristics in the same cardiomyocyte. The present study shows that H 2 O 2 activates both apoptotic and necrotic machineries in the same myocyte and that the ultrastructure seen using EM is very similar to that in I/R animal studies. The apoptotic component is caused by the activation of clotrimazole-sensitive, NAD þ /ADP ribose/poly (ADP-ribose) polymerase (PARP)-dependent transient receptor potential M2 (TRPM2) channels, which induces mitochondrial [Na þ ] m (and [Ca 2 þ ] m ) overload, resulting in mitochondrial membrane disruption, cytochrome c release, and caspase 3-dependent chromatin condensation/fragmentation. The necrotic component is caspase 3-independent and is caused by PARP-induced [ATP] i /NAD þ depletion, resulting in membrane permeabilization. Inhibition of either TRPM2 or PARP activity only partially inhibits cell death, while inhibition of both completely prevents the ultrastructural changes and myocyte death.

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Section: Discussionsupporting

confidence: 88%

“…[17][18][19] To our knowledge, this is the first report describing the molecular mechanisms involved in the two sets of death features in the same cell.…”

Section: Discussionmentioning

confidence: 88%

Section: Inhibition Of Both Trpm2 Opening and Parp Activation Preventmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

et al. 2005

Cell Death Differ

106

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“…15 Recently, Annexin A5 scintigraphy has been developed to detect early signs of cell death in humans in vivo. 16,17 Annexin A5 is an endogenous protein that binds with high affinity to negatively charged phosphatidylserine. 18 Because of an active translocase, phosphatidylserine is located almost exclusively on the inner leaflet of the lipid bilayer of the normal cell membrane.…”

Section: See P 120mentioning

confidence: 99%

Annexin A5 Scintigraphy of Forearm as a Novel In Vivo Model of Skeletal Muscle Preconditioning in Humans

et al. 2005

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Background-Nonlethal ischemia and reperfusion reduce ischemia-reperfusion-induced cell death, a phenomenon called ischemic preconditioning. In animal models, this potent endogenous protection is mimicked in vivo by administration of adenosine. In humans, exploitation of ischemic preconditioning is hindered by the lack of an appropriate in vivo model to study this phenomenon. To solve this problem, we aimed to set up an easy-to-use human in vivo model to study ischemic or pharmacological preconditioning. Methods and Results-Healthy male volunteers performed unilateral ischemic handgrip. At reperfusion, we intravenously injected technetium-99m-labeled Annexin A5, a presumed marker of ischemic injury, and we imaged both forearms and hands simultaneously with a gamma camera. Region of interest analysis (counts per pixel) and subsequent calculation of the percentage difference in radioactivity between experimental and control hands (thenar muscle; meanϮSE) revealed significant uptake to the ischemically exercised tissue (26Ϯ3% at 4 hours after reperfusion; PϽ0.05). This selective localization of Annexin A5 was reduced by ischemic preconditioning (10 minutes of ischemia plus reperfusion before ischemic exercise) or by infusion of adenosine into the brachial artery to 6Ϯ1% and 10Ϯ3%, respectively (PϽ0.05 versus ischemic exercise alone), resembling observations in animal models with infarct size as an end point.Appropriate control experiments supported our conclusion. Conclusions-Annexin

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Direct coupling of annexin A5 to VSOP yields small, protein‐covered nanoprobes for MR imaging of apoptosis

Figge

Appler

Chen

et al. 2014

Contrast Media & Molecular

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Annexin A5 (Anx) has been extensively used for imaging apoptosis by single-photon emission computed tomography, positron emission tomography, optical imaging and MRI. Recently we introduced ultrasmall Anx-VSOP (very small iron oxide particles)--the smallest high-relaxivity probe for MRI of apoptosis. Here we present a simplified method for the direct coupling of Anx to VSOP, which resulted in nanoparticles that are nearly completely covered with human Anx. These superparamagnetic nanoparticles are only 14.4 ± 2.3 nm in diameter and have higher T2* relaxivity. Compared with existing probes, the small size and the Anx shielding provide prerequisites for good biocompatibility and bioavailability in target tissues. In vitro characterization showed specific binding of Anx-VSOP to apoptotic cells, which led to a signal loss in T2*-weighted MR measurements, while control probe M1324-VSOP produced no such change. Exploratory MRI was done in vivo in a cardiac model of ischemia-reperfusion damage illustrating the potential of the probe for future studies.

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Cardiomyocyte Death Induced by Myocardial Ischemia and Reperfusion

Abstract: These data suggest that labeled annexin-V is useful for in situ detection of cell death in an in vivo model of I/R in the heart and for the evaluation of cell death-blocking strategies.

Cited by 149 publications

References 24 publications

Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

Annexin A5 Scintigraphy of Forearm as a Novel In Vivo Model of Skeletal Muscle Preconditioning in Humans

Direct coupling of annexin A5 to VSOP yields small, protein‐covered nanoprobes for MR imaging of apoptosis

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