4.5 Review

Necroptosis in heart disease: Molecular mechanisms and therapeutic implications

Journal

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 169, Issue -, Pages 74-83

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2022.05.006

Keywords

Apoptosis; Necrosis; Necroptosis; Myocardial infarction; Heart failure

Funding

  1. NIH [R01HL155035, R01HL160767]
  2. American Heart Association [19TPA34850148]

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Cell death is crucial in cardiac diseases such as ischemic injury, pathological remodeling, and heart failure. Recent studies have shown that a subset of necrotic cell death, known as regulated necrosis or necroptosis, is actively mediated through specific pathways involving death receptors and the activation of RIPK3 and MLKL. Necroptosis has been found to play an important role in myocardial homeostasis, ischemic injury, and pathological remodeling. Genetic and pharmacological interventions targeting necroptosis have shown cardioprotective effects.
Cell death is a crucial event underlying cardiac ischemic injury, pathological remodeling, and heart failure. Unlike apoptosis, necrosis had long been regarded as a passive and unregulated process. However, recent studies demonstrate that a significant subset of necrotic cell death is actively mediated through regulated pathways -a process known as regulated necrosis. As a form of regulated necrosis, necroptosis is mediated by death receptors and executed through the activation of receptor interacting protein kinase 3 (RIPK3) and its downstream substrate mixed lineage kinase-like domain (MLKL). Recent studies have provided compelling evidence that necroptosis plays an important role in myocardial homeostasis, ischemic injury, pathological remodeling, and heart failure. Moreover, it has been shown that genetic and pharmacological manipulations of the necroptosis signaling pathway elicit cardioprotective effects. Important progress has also been made regarding the molecular mechanisms that regulate necroptotic cell death in vitro and in vivo. In this review, we discuss molecular and cellular mechanisms of necroptosis, potential crosstalk between necroptosis and other cell death pathways, functional implications of necroptosis in heart disease, and new therapeutic strategies that target necroptosis signaling.

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