SIRT1 activation and its effect on intercalated disc proteins as a way to reduce doxorubicin cardiotoxicity

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  FIGURE 1. Mechanisms of doxorubicin-induced cardiomyopathy development. DOX is easily captured by cells, it undergoes one-electron reduction with the formation of a superoxide radical. The alternation of quinone and semiquinone DOX structures triggers the generation of a large amount of ROS. DOX leads to disruption of the electron transport chain, which triggers mitochondrial signaling pathways of apoptosis. The emerging oxidative stress causes an imbalance of calcium ions in the sarcoplasmic reticulum, the opening of mPTP, which ultimately activates the work of apototic caspases. DOX stimulates the accumulation of unutilized free iron in the cell, by binding to intracellular iron sequestration proteins, which enhances the ROS formation cycle. DOX and oxidative stress contribute increased production of inflammatory factors ((IL-1β), IL-6, IL-17, TNF-α) via activation of (TLR4)/MAPKs/NF-κB pathways. DOX, captured by the cell nucleus, binds to Top2β, forming a triple DOX-Top2β-DNA complex, which inhibits DNA replication, stops the cell cycle in G1 / G2 and initiates programmed cell death. ATF6/4, activating transcription factor 6/4; CHOP, C/EBP homologous protein; DOX, doxorubicin; DOXO,…

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  FIGURE 2. Schematic representation of the basic structural components of desmosome.

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  FIGURE 3. Schematic representation of the basic structural components of the adherens junctions.

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  FIGURE 4. Schematic representation of the basic structural components of the gap junction.

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  FIGURE 5. Hypothesis of the SIRT1 protective effect on myocardial ID proteins in DOX-induced cardiotoxicity. The formation of DOX-induced cardiotoxicity occurs due to the triggering of oxidative stress, inflammatory processes via the activation of TLR4/MAPKs/NF-κB pathways, and doxorubicin also inhibits the work of topoisomerase 2β. As a result, DNA damage increases, the work of cell compartments (mitochondria, sacroplasmic reticulum) is disrupted, and the structure of the myocardial ID is destroyed. Additionally, activation of DNA repair enzymes, PARPs, CD38, leads to a decrease in the functional activity of sirtuins, disruption of the work of Electron transport chain Complex I, which uses NADH as an electron donor. Damage of Complex 1 and ATP production leads to the accumulation of ROS, which increase the level of oxidative stress. Influencing SIRT1 initiates systems that reduce DOX-induced cardiotoxicity, such as antioxidant defense systems that restore mitochondrial biogenesis damaged by oxidative stress; autophagy activation systems that are disrupted by DOX, leading to accumulation of non-degradable autolysosomes; activates SIRT1/AMPK and inhibits SIRT1 p38 MAPK/NF-κB/TGF-β signaling…