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Editorial
. 2024 Nov 26;150(22):1812-1814.
doi: 10.1161/CIRCULATIONAHA.124.072172. Epub 2024 Nov 25.

Extracellular Role for the Intracellular Cell Death Mediator RIPK3 in Myocardial Infarction

Dongze Qin #  1 , Radheshyam Modanwal #  1 , Richard N Kitsis  1
Affiliations
Editorial

Extracellular Role for the Intracellular Cell Death Mediator RIPK3 in Myocardial Infarction

Dongze Qin et al. Circulation. .
No abstract available

Keywords: CaMKII; DAMP; Editorials; MACE; RIPK3; biomarkers; cell death; inflammation; myocardial infarction; necroptosis.

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Conflict of interest statement

None.

Figures

Figure.
Figure.. Necroptosis pathway and model proposed for signaling by extracellular RIPK3 (receptor-interacting serine/threonine-protein kinase 3) during reperfused myocardial infarction (MI/R).
Necroptosis is a regulated necrosis program defined by a core pathway in which RIPK3 phosphorylates MLKL (mixed lineage kinase domain-like). Phosphorylated MLKL then disrupts plasma membrane integrity (not shown; see text for details). The kinase activity of RIPK3 is activated by interactions of RIPK3 with RIPK1, ZBP1 (Z-DNA binding protein 1), and TRIF (TIR (toll/interleukin-1 receptor) domain-containing adaptor inducing IFN (interferon)-β), relaying various subsets of cell death signals (see text). In some cells, including cardiomyocytes, RIPK3 can also phosphorylate and activate CaMKII (Ca2+/calmodulin-dependent protein kinase II) triggering mitochondrial permeability transition (MPT)-driven cell death, a second necrosis program. In addition to necroptosis which requires RIPK3 kinase function, RIPK3 can also stimulate apoptosis and inflammatory signaling through its scaffold (not shown). The study proposes that RIPK3 is actively secreted from cardiomyocytes through a Ca2+/ synaptotagmin 7 (Syt7)-dependent mechanism. It is not known whether secreted RIPK3 is phosphorylated. Extracellular RIPK3 is proposed to bind RAGE (receptor for advanced glycation endproducts), which interacts with β1-adrenergic receptor, resulting in the elevation of intracellular Ca2+ concentration, CaMKII phosphorylation and activation, and cell death.
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Comment on

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