Necrostatin: A Potentially Novel Cardioprotective Agent?

Smith, Christopher; Davidson, Sean M.; Lim, Shiang Y.; Simpkin, James C.; Hothersall, John S.; Yellon, Derek M.

doi:10.1007/s10557-007-6035-1

Cited by 297 publications

(210 citation statements)

References 24 publications

Supporting

Mentioning

195

Contrasting

Unclassified

Order By: Relevance

“…The mode of cell death of tubular cells in acute kidney injury (AKI) has been a matter of intense discussion (21,22). Because RIPK3-deficient mice have been shown to be partially protected from IRI-induced tubular necrosis (4, 23) and because Nec-1 phenocopies this effect (21,24,25), it was hypothesized that necroptosis might be the mode of cell death that drives parenchymal cells into necrosis. However, it was not ruled out that tubular cell death might have occurred secondary to some changes outside the tubular compartment: e.g., in RIPK3-dependent organ perfusion, which might be altered also upon Nec-1 treatment if the necroptotic pathway was involved.…”

Section: Resultsmentioning

confidence: 99%

Synchronized renal tubular cell death involves ferroptosis

Linkermann

Skouta

Himmerkus

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

907

804

View full text Add to dashboard Cite

Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, irondependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the firstin-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

Synchronized renal tubular cell death involves ferroptosis

Linkermann

Skouta

Himmerkus

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

907

804

View full text Add to dashboard Cite

show abstract

“…Necroptosis shares with necrosis the fact that dying cells display the morphological features of necrosis but not of apoptosis, but is highly regulated by an intracellular protein platform 14, 16. Recent advances have shown that activation of the kinase domain of receptor‐interacting protein1 (RIP1) and the assembly of RIP1/3‐containing signalling complex (termed the necrosome) mediated necroptosis contributes to the pathogenesis in preclinical models of brain 17, 18, heart 19, 20, and kidney 21, 22 I/R injury, which can be protected by using the RIP1 kinase inhibitor necrostatin (Nec)‐1. Meanwhile, the necrosome phosphorylates the mixed lineage kinase domain‐like protein (MLKL), which subsequently results in the rapid, active, and dynamic release of cell damage‐associated molecular patterns (DAMPs) following the loss of plasma membrane integrity and promotes ongoing inflammation and secondary tissue injury 23.…”

Section: Introductionmentioning

confidence: 99%

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

Wen

Ling

Yang

et al. 2016

J Cellular Molecular Medi

View full text Add to dashboard Cite

Cell death is an important biological process that is believed to have a central role in intestinal ischaemia/reperfusion (I/R) injury. While the apoptosis inhibition is pivotal in preventing intestinal I/R, how necrotic cell death is regulated remains unknown. Necroptosis represents a newly discovered form of programmed cell death that combines the features of both apoptosis and necrosis, and it has been implicated in the development of a range of inflammatory diseases. Here, we show that receptor‐interacting protein 1/3 (RIP1/3) kinase and mixed lineage kinase domain‐like protein recruitment mediates necroptosis in a rat model of ischaemic intestinal injury in vivo. Furthermore, necroptosis was specifically blocked by the RIP1 kinase inhibitor necrostatin‐1. In addition, the combined treatment of necrostatin‐1 and the pan‐caspase inhibitor Z‐VAD acted synergistically to protect against intestinal I/R injury, and these two pathways can be converted to one another when one is inhibited. In vitro, necrostatin‐1 pre‐treatment reduced the necroptotic death of oxygen‐glucose deprivation challenged intestinal epithelial cell‐6 cells, which in turn dampened the production of pro‐inflammatory cytokines (tumour necrosis factor‐α and interleukin‐1β), and suppressed high‐mobility group box‐1 (HMGB1) translocation from the nucleus to the cytoplasm and the subsequent release of HMGB1 into the supernatant, thus decreasing the activation of Toll‐like receptor 4 and the receptor for advanced glycation end products. Collectively, our study reveals a robust RIP1/RIP3‐dependent necroptosis pathway in intestinal I/R‐induced intestinal injury in vivo and in vitro and suggests that the HMGB1 signalling is highly involved in this process, making it a novel therapeutic target for acute ischaemic intestinal injury.

show abstract

“…Distinguishing these mechanisms of cell death could be crucial in transplantation as necroptosis is phenotypically similar to necrosis and may play a central role in allograft rejection by enhancing the release of proinflammatory danger molecules and promoting inflammatory injury in the graft. Necroptosis has been implicated in a variety of diseases and necrostatin-1 (Nec-1) treatment has been shown to prevent organ injury in models of cerebral cortex infarction (22), chronic intestinal inflammation (23), ethanol-induced liver injury (24), myocardial infarction (25), ischemia-reperfusion injury in the kidney (26) and heart (27), and renal transplantation (28). Hence, necroptosis may be an important link in transplant rejection (29).…”

Section: Introductionmentioning

confidence: 99%

RIPK3-Mediated Necroptosis Regulates Cardiac Allograft Rejection

Pavlosky

Lau

et al. 2014

American Journal of Transplantation

View full text Add to dashboard Cite

Cell death results in tissue damage and ultimately donor graft rejection and can occur as an active molecular process through apoptotic, necrotic and newly identified receptor interacting protein 1 and 3 kinase (RIPK1/3)-mediated necroptotic pathways. Necroptosis leads to the release of inflammatory molecules which can activate host immune cells. This pathway has yet to be studied in heart transplantation. We have found that necroptosis was induced in murine cardiac microvascular endothelial cell (MVEC) under anti-apoptotic condition following tumor necrosis factor alpha treatment. Necroptotic cell death and release of the danger molecule high mobility group box 1 (HMGB1) were inhibited by the RIPK1 inhibiting molecule necrostatin-1 and by genetic deletion of RIPK3. In addition, tissue necrosis, release of HMGB1 and graft cell infiltrate were attenuated in RIPK3 null heart allografts following transplantation. Finally, a brief sirolimus treatment markedly prolonged RIPK3 null cardiac allograft survival in allogeneic BALB/c recipients as compared to WT C57BL/6 donor grafts (95 AE 5.8 vs. 24 AE 2.6 days, p < 0.05). This study has demonstrated that RIPK1/3 contributes to MVEC death and cardiac allograft survival through necroptotic death and the release of danger molecules. Our results suggest that targeting RIPKmediated necroptosis may be an important therapeutic strategy in transplantation.

show abstract

Necrostatin: A Potentially Novel Cardioprotective Agent?

Abstract: This is the first study to demonstrate that necrostatins inhibit myocardial cell death and reduce infarct size, possibly via a mechanism independent of the MPTP.

Cited by 297 publications

References 24 publications

Synchronized renal tubular cell death involves ferroptosis

Synchronized renal tubular cell death involves ferroptosis

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

RIPK3-Mediated Necroptosis Regulates Cardiac Allograft Rejection

Contact Info

Product

Resources

About