Nekroptozis: Serebral ve Miyokardiyal İskemi/Reperfüzyon Hasarı için Terapötik bir Hedef midir?

Öz

Programlı bir hücre ölümü olan nekroptozun, iskemi/reperfüzyon (İ/R) hasarına olan katkısını ve kesin önemini tanımlamak için kapsamlı araştırma çalışmaları yürütülmüştür. Bu hücre hasarı süreci, serebral iskemik inme ve miyokard infarktüsünün patofizyolojisinde kritik bir rol oynamaktadır. Böylece, reseptörle etkileşen protein kinazları (RIP1 ve RIP3) ve karışık soy kinaz alanı benzeri psödokinazı (MLKL) içeren nekroptozun kanonik sinyal yolunun bileşenlerinin modülasyonunun nöroprotektif ve kardiyoprotektif etkiler ortaya çıkardığı belgelenmiştir. Bu koruyucu etkiler, infarkt boyutunun küçülmesi ve nörolojik defisitlerin, miyokardiyal disfonksiyonun ve olumsuz kardiyak yeniden şekillenmenin hafifletilmesi ile kanıtlanmaktadır. Son zamanlarda, serebral ve miyokardiyal İ/R hasarında nekroptozun RIPK1-RIPK3-MLKL kanonik moleküler sinyalizasyonuna ek olarak, RIPK3'ün kalmodulin bağımlı protein kinaz IIδ (CaMKIIδ), fosfogliserat mutaz 5 (PGAM5), dynamin-related protein 1 (Drp-1), apoptozu indükleyen faktör (AİF), ksantin oksidaz (XO) ve ölümle ilişkili protein (DAXX) gibi aşağı akış molekülleri etkilediği gösterilerek nekroptozun kanonik olmayan yolları tanımlanmıştır. Bu derlemede serebral ve miyokardiyal İ/R hasarında nekroptozun rolü ve nekroptozu baskılayan farmakolojik ajanların ve genetik modifikasyonların bu hasar üzerine terapötik etkileri ile ilgili in vitro ve in vivo deneysel modellerden elde edilen kanıtlar özetlenmekte ve tartışılmaktadır.

Anahtar Kelimeler

• Serebral
• Miyokardiyal
• İskemi/reperfüzyon hasarı
• Nekroptozis
• RIPK1
• RIPK3
• MLKL

Necroptosis: A Therapeutic Target for Cerebral and Myocardial Ischaemia/Reperfusion Injury?

Öz

Extensive research studies have been conducted to define the contribution and exact significance of necroptosis, a programmed cell death, to ischaemia/reperfusion (I/R) injury. This cell damaging process plays a critical role in the pathophysiology of cerebral ischemic stroke and myocardial infarction. Thus, it has been documented that modulation of components of the canonical signalling pathway of necroptosis involving receptor-interacting protein kinases (RIP1 and RIP3) and mixed lineage kinase domain-like pseudokinase (MLKL) elicits neuroprotective and cardioprotective effects. These protective effects are evidenced by the reduction of infarct size, alleviation of neurological deficits, myocardial dysfunction, and adverse cardiac remodeling. Recently, in addition to RIPK1-RIPK3-MLKL canonical molecular signalling of necroptosis in cerebral and myocardial I/R injury, non-canonical pathways of necroptosis have been identified by showing that RIPK3 affects downstream molecules such as calmodulin-dependent protein kinase IIδ (CaMKIIδ), phosphoglycerate mutase 5 (PGAM5), dynamin-related protein 1 (Drp-1), apoptosis-inducing factor (AIF), xanthine oxidase and death-associated protein (DAXX). This review summarises and discusses evidence from in vitro and in vivo experimental models regarding the role of necroptosis in cerebral and myocardial I/R injury and the therapeutic effects of pharmacological agents and genetic modifications that suppress necroptosis on this injury.

Anahtar Kelimeler

• Cerebral
• Myocardial
• Ischemia/reperfusion injury
• Necroptosis
• RIPK1
• RIPK3
• MLKL

Kaynakça

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