Poxvirus-derived cytokine response modifier A (CrmA) does not protect against focal cerebral ischemia in mice

Kılıç, Ertuğrul; Wippel, Andreas; Kılıç, Ülkan; Vogel, Peter; Kim, Mia; Putten, Herman van der; Wiessner, Christoph; Rovelli, Giorgio; Böttiger, Bernd W.; Hermann, Dirk M.

doi:10.1016/j.brainres.2007.09.031

Cited by 4 publications

(6 citation statements)

References 25 publications

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“…stable transfection of target cells (27). Among others, Kilic et al designed crmA transgenic mice that remained healthy and did not differ from wild-type mice in any of the evaluated parameters (28). When the crmA transgenic mice underwent stroke due to occlusion of the middle cerebral artery, no difference in infarction size could be detected compared with wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

Effective Blockage of Both the Extrinsic and Intrinsic Pathways of Apoptosis in Mice by TAT-crmA

Krautwald

Ziegler²,

Rölver³

et al. 2010

Journal of Biological Chemistry

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Evidence accumulates that in clinically relevant cell death, both the intrinsic and extrinsic apoptotic pathway synergistically contribute to organ failure. In search for an inhibitor of apoptosis that provides effective blockage of these pathways, we analyzed viral proteins that evolved to protect the infected host cells. In particular, the cowpox virus protein crmA has been demonstrated to be capable of blocking key caspases of both pro-apoptotic pathways. To deliver crmA into eukaryotic cells, we fused the TAT protein transduction domain of HIV to the N terminus of crmA. In vitro, the TAT-crmA fusion protein was efficiently translocated into target cells and inhibited apoptosis mediated through caspase-8, caspase-9, and caspase-3 after stimulation with ␣-Fas, etoposide, doxorubicin, or staurosporine. The extrinsic apoptotic pathway was investigated following ␣-Fas stimulation. In vivo 90% of TAT-crmA-treated animals survived an otherwise lethal dose of ␣-Fas and showed protection from Fas-induced organ failure. To examine the intrinsic apoptotic pathway, we investigated the survival of mice treated with an otherwise lethal dose of doxorubicin. Whereas all control mice died within 31 days, 40% of mice that concomitantly received intraperitoneal injections of TAT-crmA survived. To test the ability to comprehensively block both the intrinsic and extrinsic apoptotic pathway in a clinically relevant setting, we employed a murine cardiac ischemia-reperfusion model. TAT-crmA reduced infarction size by 40% and preserved left ventricular function. In summary, these results provide a proof of principle for the inhibition of apoptosis with TAT-crmA, which might provide a new treatment option for ischemia-reperfusion injuries.Apoptotic processes are centrally involved during organogenesis in complex organisms but may also cause organ failure in response to a variety of harmful stimuli. Certain infectious diseases, intoxications, or fulminant immune responses may trigger an overwhelming apoptotic response (1). Moreover, minimizing apoptotic organ failure due to ischemia-reperfusion injuries that occur during stroke or myocardial infarction remains a major challenge in clinical settings. Each year, ϳ1.5 million myocardial infarction cases are recorded in the United States. Myocardial infarction is the leading cause of death in both Europe and the United States. Therefore, transient blockage of apoptosis is of clinical importance to protect cardiac function and to save lives.Apoptosis is controlled by the extrinsic death receptor pathway and the intrinsic mitochondrial pathway. Notably, both pathways converge at caspase-3, leading to activation of other proteases. Caspases have more than 400 different substrates that interfere with transcription, translation, DNA cleavage, cytoskeleton assembly, and membrane trafficking. To prevent this "death by a thousand cuts," it is important to block caspases in both the intrinsic and extrinsic pathways as well as caspases involved in the execution process of apoptosis (2). The extrins...

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Section: Discussionmentioning

confidence: 99%

Effective Blockage of Both the Extrinsic and Intrinsic Pathways of Apoptosis in Mice by TAT-crmA

Krautwald

Ziegler²,

Rölver³

et al. 2010

Journal of Biological Chemistry

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“…77 In contrast, RIPK3 deficiency was not protective in this model. 79, 80 We understand today that all forms of regulated necrosis are positive for TUNEL in vivo. 79, 80 We understand today that all forms of regulated necrosis are positive for TUNEL in vivo.…”

Section: Ischemia-reperfusion Injury and Necrostatinsmentioning

confidence: 99%

“…TNFα neutralization moderately protected mice in the most commonly used model of cerulein-induced pancreatitis (CIP). 13,79 It is well known from clinical practice that low levels of Ca 2+ correlate to some extent with pancreas tissue necrosis and therefore represent a prognostic marker of severe disease; interestingly, Ca 2+ release-inhibitor dantrolene, which has also been described to inhibit necroptosis, strongly reduced TUNEL-positive cells. 24,25 These data, however, could not be reproduced by at least two other groups.…”

Section: Necroptosis and The Gastrointestinal Systemmentioning

confidence: 99%

“…78 However, earlier reports of beneficial apoptosis reduction exist, but were not conclusive as they had been based on TUNEL assays for the detection of apoptosis. 79,80 We understand today that all forms of regulated necrosis are positive for TUNEL in vivo. Therefore, we can only conclude that a Nec-1-sensitive cell death is probably a major contributor to ischemic injury.…”

Section: Ischemia-reperfusion Injury and Necrostatinsmentioning

confidence: 99%

“…24,25 These data, however, could not be reproduced by at least two other groups. 13,79 It is well known from clinical practice that low levels of Ca 2+ correlate to some extent with pancreas tissue necrosis and therefore represent a prognostic marker of severe disease; interestingly, Ca 2+ release-inhibitor dantrolene, which has also been described to inhibit necroptosis, strongly reduced TUNEL-positive cells. 153 However, in the same model, Nec-1 exacerbated rather than protected from CIP.…”

Section: Necroptosis and The Gastrointestinal Systemmentioning

confidence: 99%

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The in vivo evidence for regulated necrosis

Tonnus

Linkermann

2017

Immunological Reviews

102

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Necrosis is a hallmark of several widespread diseases or their direct complications. In the past decade, we learned that necrosis can be a regulated process that is potentially druggable. RIPK3- and MLKL-mediated necroptosis represents by far the best studied pathway of regulated necrosis. During necroptosis, the release of damage-associated molecular patterns (DAMPs) drives a phenomenon referred to as necroinflammation, a common consequence of necrosis. However, most studies of regulated necrosis investigated cell lines in vitro in a cell autonomous manner, which represents a non-physiological situation. Conclusions based on such work might not necessarily be transferrable to disease states in which synchronized, non-cell autonomous effects occur. Here, we summarize the current knowledge of the pathophysiological relevance of necroptosis in vivo, and in light of this understanding, we reassess the morphological classification of necrosis that is generally used by pathologists. Along these lines, we discuss the paucity of data implicating necroptosis in human disease. Finally, the in vivo relevance of non-necroptotic forms of necrosis, such as ferroptosis, is addressed.

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