Annexin-V imaging for noninvasive detection of cardiac allograft rejection

Narula, Jagat; Er, Acio; Narula, Navneet; Le, Samuels; Fyfe, Billie; Wood, David P.; Jm, Fitzpatrick; Pn, Raghunath; Je, Tomaszewski; Kelly, Crystal; Steinmetz, Neil; A, Green; Jf, Tait; Leppo, Jeffrey A.; Fg, Blankenberg; Jain, Diwakar; Hw, Strauss

doi:10.1038/nm1201-1347

Cited by 293 publications

(170 citation statements)

References 15 publications

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“…[1][2][3][4] Postnatal cardiomyocytes are terminally differentiated cells that are not able to divide at a rate allowing for the replacement of dead cells. 5 Ongoing cellular loss in these conditions could be a determining factor in the progression to heart failure, 6 although the relative contribution of the apoptotic pathways has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Lack of Apaf-1 expression confers resistance to cytochrome c-driven apoptosis in cardiomyocytes

et al. 2003

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Apoptosis plays a role in cardiomyocyte death in several cardiovascular disorders. Here, we show that primary postnatal cardiomyocytes did not die upon activation of the intrinsic (cytochrome c-dependent) apoptotic pathway. Release of cytochrome c from mitochondria to the cytosol occurred, but did not activate the effector phase of apoptosis. Myocardial cells did not express apoptotic protease-activating factor-1 (Apaf-1), the allosteric activator of caspase-9 acting downstream of cytochrome c release. Forced expression of Apaf-1 restored the competence to complete the cytochrome c-induced apoptotic program and this effect was prevented by overexpression of Bcl-X L . However, cardiomyocytes were able to enter the apoptotic program when it was initiated by activation of death receptors, as observed during serum deprivation and metabolic inhibition. Our results indicate that regulation of Apaf-1 expression may be a new regulatory mechanism developed in postmitotic cells in order to prevent irreversible commitment to die after release of cytochrome c.

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Section: Introductionmentioning

confidence: 99%

Lack of Apaf-1 expression confers resistance to cytochrome c-driven apoptosis in cardiomyocytes

et al. 2003

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“…When it is bound to the phosphatidylserine it can be used to detect the apoptosis in vivo. Technetium-99m-labeled annexin-V is a promising method for assessing the degree of apoptosis [15][16][17]. In this study we used this technology to measure myocardial apoptosis with great success.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, the injury can also occur during the reperfusion. In addition to myocardial necrosis, apoptosis makes a significant contribution to cell death following acute myocardial ischemia and it is particularly enhanced during reperfusion [14,15]. Phosphatidylserine, a phospholipid that is normally confined to the inner leaflet of cell membrane bilayer, becomes exteriorized during the process of apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…Annexin-V is an endogenous protein that has a high affinity for binding to phosphatidylserine. Technetium99m-labeled annexin-V is a promising method to assess the degrees of apoptosis [15][16][17]. By using 3 different technologies, real-time imaging of technetium-99m-labeled annexin-V, transferase dUTP nick end labeling (TUNEL) assay, and caspase-3, we test the hypothesis that delayed APC with sevoflurane can attenuate myocardial apoptosis during I/R.…”

Section: Introductionmentioning

confidence: 99%

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The changes of technetium-99m-labeled annexin-V in delayed anesthetic preconditioning during myocardial ischemia/reperfusion

et al. 2013

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This study was designed to use real-time imaging to test the hypothesis that delayed cardiac protection induced by volatile anesthetics inhibits apoptosis. Rats were divided into two groups. One group was exposed to 120 min of 33 % O 2 [control group (CON group)] and the other group was exposed to 2.5 % sevoflurane in 33 % O 2 for 120 min [sevoflurane group (SEVO group)]. Both groups were allowed to return to their cages for 24 h. After 24 h recovery, all rats underwent 30 min myocardial ischemia by occluding coronary artery followed by 2 h of reperfusion. After reperfusion, technetium-99m-labeled annexin-V was administered intravenously to identify apoptosis. Left ventricular samples were obtained to measure infarct size and radionuclide imaging and caspase-3. Radionuclide imaging indicated that apoptosis was reduced in SEVO group (0.78 % ± 0.82) when compared with the CON group (1.15 % ± 0.61), and the infarct size was also decreased in the SEVO group (40 % ± 7). The transferase dUTP nick end labeling (TUNEL)-positive cardiomyocytes in the SEVO group (16 % ± 6) were significantly decreased in the peri-infarct zone when compared with the CON group (28 % ± 4). After reperfusion, caspase-3 expression was significantly blunted in the SEVO group than in CON group (50 % ± 11 vs. 68 % ± 10, p \ 0.05). This study used technetium-99m-labeled annexin-V of real-time imaging to detect cardiomyocyte apoptosis and the results were confirmed by the TUNEL assay and caspase-3 expression. We concluded that delayed volatile anesthetic preconditioning (APC) protects against I/R in vivo. The method of technetium-99m-labeled annexin-V of real-time imaging can be used to detect cardiomyocyte apoptosis in delayed APC during ischemia/reperfusion.

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“…26 Furthermore, the recent administration of technetium-99m-labeled annexin V to human cardiac allograft recipients has revealed the clinical feasibility and safety of annexin V imaging for detection of transplant rejection. 27 Radio-labeled annexin V is now entering clinical trials for the assessment of therapeutic efficacy in cancer patients, the extent and severity of myocardial infarction, and the screening for acute rejection in heart transplant recipients, and could perhaps serve to obviate invasive biopsies in some cases. However, the clinical usefulness of the annexin V-based imaging method depends, of course, on whether apoptotic and nonapoptotic PS externalization can be discriminated with sufficient accuracy.…”

Section: Monitoring Death In the Livingmentioning

confidence: 99%

PS externalization: from corpse clearance to drug delivery

Fadeel¹,

Xue²

2005

Cell Death Differ

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Phosphatidylserine (PS) externalization on the plasma membrane of aging red blood cells and on apoptotic cell corpses serves as a common recognition signal for macrophages. 1 Perturbation of phospholipid asymmetry and rapid redistribution of PS also occurs in platelets and provides a procoagulant surface that promotes blood clotting. 2 In addition, several recent studies have revealed novel roles for altered plasma membrane phospholipid distribution in nonapoptotic cells. The aim of the present discourse is to highlight these emerging roles for PS externalization, and some of the putative therapeutic implications thereof. PS signaling is required for programmed cell clearancePhospholipid asymmetry is a common feature of all eukaryotic membranes. Moreover, mitotic and quiescent cells invest considerable amounts of energy to generate and maintain membrane lipid sidedness. Loss of phospholipid asymmetry and the concomitant externalization of PS can be readily monitored by the use of fluorescence-conjugated annexin V, an endogenous protein that specifically binds to PS, and this process has been well studied in platelets. Thus, when platelets are activated by agonists, such as thrombin and collagen, PS is rapidly brought to the surface of the cell. Exposed PS then catalyzes the assembly of proteins of the coagulation system, leading to a conversion of soluble fibrinogen into an insoluble fibrin clot. 2 The pivotal role of PS externalization is illustrated in Scott syndrome, a bleeding disorder characterized by an impaired Ca 2 þ -induced phospholipid scrambling, and hence an inability of platelets to promote blood coagulation. 2 Apoptotic cells are also procoagulant, and annexin V can completely abolish the procoagulant activity, suggesting that this effect is PS-dependent. 3 More recent findings suggest that annexin V-induced internalization of tissue factor (TF), the initiator of blood coagulation, may also contribute to the anticoagulant functions of annexin V (discussed below).The ability of PS to act as a signal for in vivo recognition and clearance of effete cells was demonstrated 20 years ago in studies of red blood cells. 4 Subsequent studies by Fadok et al. 5 showed that PS externalization also can trigger specific recognition and removal of apoptotic cells, and the exposition of PS was soon found to be a common, if not universal, event during apoptosis. 6 More recent studies have shown that PS externalization is, in fact, essential for corpse clearance by macrophages and nonprofessional phagocytes (fibroblasts). 1 Moreover, our studies have indicated that the generation of oxidized PS species (PS-OX) is an integral part of the apoptosis program. 7 Externalization of PS-OX on the cell surface potentiates macrophage engulfment of apoptotic cells, and could also serve to promote the binding of so-called bridging molecules (serum proteins) to apoptotic cell corpses. 8 Interestingly, deletion in mice of the PS-binding bridging molecule, milk fat globule epidermal growth factor 8 (MFG-E8) (also known as lactadhe...

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Annexin-V imaging for noninvasive detection of cardiac allograft rejection

Cited by 293 publications

References 15 publications

Lack of Apaf-1 expression confers resistance to cytochrome c-driven apoptosis in cardiomyocytes

Lack of Apaf-1 expression confers resistance to cytochrome c-driven apoptosis in cardiomyocytes

The changes of technetium-99m-labeled annexin-V in delayed anesthetic preconditioning during myocardial ischemia/reperfusion

PS externalization: from corpse clearance to drug delivery

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