Fundamental mechanisms of regulated cell death and implications for heart disease

Dominic P. Del Re, Dulguun Amgalan, Andreas Linkermann, Qinghang Liu, Richard N. Kitsis

Research output: Contribution to journalArticle

Abstract

Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death play important roles in both myocardial infarction with reperfusion (ischemia/reperfusion) and heart failure. While a role for apoptosis in ischemia/reperfusion cannot be excluded, regulated forms of necrosis, through both death receptor and mitochondrial pathways, are critical. Ferroptosis and parthanatos are also likely important in ischemia/reperfusion, although it is unclear if these entities are functioning as independent death programs or as amplification mechanisms for necrotic cell death. Pyroptosis may also contribute to ischemia/reperfusion injury, but potentially through effects in non-cardio-myocytes. Cardiomyocyte loss through apoptosis and necrosis is also an important component in the pathogenesis of heart failure and is mediated by both death receptor and mitochondrial signaling. Roles for immunogenic cell death in cardiac disease remain to be defined but merit study in this era of immune checkpoint cancer therapy. Biology-based approaches to inhibit cell death in the various cardiac syndromes are also discussed.

Original languageEnglish (US)
Pages (from-to)1765-1817
Number of pages53
JournalPhysiological Reviews
Volume99
Issue number4
DOIs
StatePublished - Jul 1 2019

Fingerprint

Heart Diseases
Cell Death
Death Domain Receptors
Reperfusion
Heart Failure
Apoptosis
Ischemia
Cardiac Myocytes
Myocardial Infarction
Critical Pathways
Autophagy
Reperfusion Injury
Muscle Cells
Dissection
Neoplasms

Keywords

  • Apoptosis
  • Cell death
  • Heart disease
  • Necroptosis
  • Necrosis

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Physiology (medical)

Cite this

Fundamental mechanisms of regulated cell death and implications for heart disease. / Del Re, Dominic P.; Amgalan, Dulguun; Linkermann, Andreas; Liu, Qinghang; Kitsis, Richard N.

In: Physiological Reviews, Vol. 99, No. 4, 01.07.2019, p. 1765-1817.

Research output: Contribution to journalArticle

Del Re, Dominic P. ; Amgalan, Dulguun ; Linkermann, Andreas ; Liu, Qinghang ; Kitsis, Richard N. / Fundamental mechanisms of regulated cell death and implications for heart disease. In: Physiological Reviews. 2019 ; Vol. 99, No. 4. pp. 1765-1817.
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