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Review
. 2023 Dec 15:11:1309719.
doi: 10.3389/fcell.2023.1309719. eCollection 2023.

Current insight on the mechanisms of programmed cell death in sepsis-induced myocardial dysfunction

Affiliations
Review

Current insight on the mechanisms of programmed cell death in sepsis-induced myocardial dysfunction

An-Bu Liu et al. Front Cell Dev Biol. .

Abstract

Sepsis is a clinical syndrome characterized by a dysregulated host response to infection, leading to life-threatening organ dysfunction. It is a high-fatality condition associated with a complex interplay of immune and inflammatory responses that can cause severe harm to vital organs. Sepsis-induced myocardial injury (SIMI), as a severe complication of sepsis, significantly affects the prognosis of septic patients and shortens their survival time. For the sake of better administrating hospitalized patients with sepsis, it is necessary to understand the specific mechanisms of SIMI. To date, multiple studies have shown that programmed cell death (PCD) may play an essential role in myocardial injury in sepsis, offering new strategies and insights for the therapeutic aspects of SIMI. This review aims to elucidate the role of cardiomyocyte's programmed death in the pathophysiological mechanisms of SIMI, with a particular focus on the classical pathways, key molecules, and signaling transduction of PCD. It will explore the role of the cross-interaction between different patterns of PCD in SIMI, providing a new theoretical basis for multi-target treatments for SIMI.

Keywords: complication; infection; multi-target treatment; programmed cell death (PCD); sepsis induced myocardial injury (SIMI).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Programmed Cell Death in Myocardial Injury Induced by Sepsis (SIMI). In SIMI, programmed cell death can be categorized into caspase-dependent cell death, which includes apoptosis and pyroptosis, and non-caspase-dependent cell death, which includes ferroptosis and autophagy.
FIGURE 2
FIGURE 2
Main Pathways of Apoptosis. Pathway of apoptosis can be divided in extrinsic and intrinsic apoptotic cascade pathway. Extrinsic apoptotic cascade pathway is primarily activated through the specific activation TRADD receptors and caspase-8. Intrinsic apoptotic cascade pathway can be triggered by the release of cytochrome c and SMAC, which subsequently leads to increasing expression of pro-apoptotic protein Bax and induces cell apoptosis. Moreover, the combination of released cyto-c with Apaf-1 and caspase-9 also triggers exogenous apoptotic cascade reactions.
FIGURE 3
FIGURE 3
Main Signaling Pathways of Apoptosis. MAPK and TLR/NF-κB pathway can activate apoptosis. PI3K/AKT/mTOR pathway can inhibit apoptosis.
FIGURE 4
FIGURE 4
Main Pathways of Necroptosis. Necroptosis can be mainly regulated by RIPK1 and RIPK3, which can form necrosome and inhibition of caspase-8 and cIAPs. The necrosome trigger phosphorylation of MLKL and enables it to form pores in the membrane. These MLKL pores allows for ion efflux, cellular swelling, membrane rupture, and subsequent uncontrolled release of intracellular contents, ultimately resulting in necroptosis. Furthermore, pathogenic microorganisms can release cytoplasmic DNA and combine ZBPI, recruiting RIPK3, activating MLKL and forming necrotic complex, which contributes to necroptosis. cIAPs, cellular inhibitor of apoptosis proteins; TRAIL, TNF-related apoptosis-inducing ligand; TRAILR, receptor of TNF-related apoptosis-inducing ligand; ZBPI, Z-DNA binding protein 1; DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns.
FIGURE 5
FIGURE 5
Main Pathways of Pyroptosis. Pyroptosis can be categorized into two types depending on whether they are caspase1 dependent or not. In caspase-1 dependent pyroptosis, the process is initiated by the assembly of inflammasomes. In caspase-1 non-dependent pyroptosis can be triggered by the interaction between caspase4, caspase5, or caspase11 (depending on the species) and LPS.
FIGURE 6
FIGURE 6
Main Pathways of Ferroptosis. Cystine is transported into the cell by System Xc-for synthesis of GSH, which can be used by GPX4 as a substrate to prevent lipid ROS accumulation. And lipid peroxidation also could be inhibited by CoQ10 generated from MVA. Consequently, the accumulation of lipid ROS triggers ferroptosis.
FIGURE 7
FIGURE 7
Main Signaling pathways of Autophagy. AMPK pathway can activate autophagy. PI3K/AKT/mTOR pathway can inhibit autophagy.
FIGURE 8
FIGURE 8
Interaction of Programmed Cell Death Pathways in SIMI. TLR4 involves pyroptosis, apoptosis and necroptosis. Activation of RIPK1 regulates necroptosis and induces apoptosis under oxidative stress and inflammatory processes. Beclin-1 regulates autophagy and apoptosis during infection. P38 MAPK pathway can inhibit necroptosis by inhibiting MLKL activation and regulates autophagy, ferroptosis and pyroptosis by regulating expression of SIRT1. NF-κB can regulate apoptosis, pyroptosis and ferroptosis. GSDMD in pyroptosis and necrosome in necroptosis can cooperate to amplify inflammatory signals.

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