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Review
. 2022 Nov 4:13:1035387.
doi: 10.3389/fphar.2022.1035387. eCollection 2022.

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

Ekaterina Podyacheva  1 , Yana Toropova  1
Affiliations
Review

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

Ekaterina Podyacheva et al. Front Pharmacol. .

Erratum in

Abstract

According to the World Health Organization, the neoplasm is one of the main reasons for morbidity and mortality worldwide. At the same time, application of cytostatic drugs like an independent type of cancer treatment and in combination with surgical methods, is often associated with the development of cardiovascular complications both in the early and in the delayed period of treatment. Doxorubicin (DOX) is the most commonly used cytotoxic anthracycline antibiotic. DOX can cause both acute and delayed side effects. The problem is still not solved, as evidenced by the continued activity of researchers in terms of developing approaches for the prevention and treatment of cardiovascular complications. It is known, the heart muscle consists of cardiomyocytes connected by intercalated discs (ID), which ensure the structural, electrical, metabolic unity of the heart. Various defects in the ID proteins can lead to the development of cardiovascular diseases of various etiologies, including DOX-induced cardiomyopathy. The search for ways to influence the functioning of ID proteins of the cardiac muscle can become the basis for the creation of new therapeutic approaches to the treatment and prevention of cardiac pathologies. SIRT1 may be an interesting cardioprotective variant due to its wide functional significance. SIRT1 activation triggers nuclear transcription programs that increase the efficiency of cellular, mitochondrial metabolism, increases resistance to oxidative stress, and promotes cell survival. It can be assumed that SIRT1 can not only provide a protective effect at the cardiomyocytes level, leading to an improvement in mitochondrial and metabolic functions, reducing the effects of oxidative stress and inflammatory processes, but also have a protective effect on the functioning of IDs structures of the cardiac muscle.

Keywords: NAD+; adherens junctions; desmosomes; doxorubicin cardiomyopathy; gap junction; heart failure; intercalated discs; sirtuins.

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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
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, semiquinone form of doxorubicin; ETC, electron transport chain; GRP78, 78-kDa glucose-regulated protein precursor; IL-6/17/1β, interleukin 6/17/1β; IRE-BP, iron-responsive element-binding proteins; MAPKs, mitogen-activated protein kinases; mPTP, mitochondrial permeability transition pore; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PERK, (PKR)-like endoplasmic reticulum kinase; ROS, reactive oxygen species; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor; Top2β, topoisomerase 2β.
FIGURE 2
FIGURE 2
Schematic representation of the basic structural components of desmosome.
FIGURE 3
FIGURE 3
Schematic representation of the basic structural components of the adherens junctions.
FIGURE 4
FIGURE 4
Schematic representation of the basic structural components of the gap junction.
FIGURE 5
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 pathways that contribute to the normalization of the regulation of inflammatory responses, improve the functioning of ID structures, modulate apoptotic processes, and exert antifibrotic regulation. It is interesting to note the possible role of SIRT1 in the regulation of switching between the processes of necroptosis, pyroptosis, and apoptosis. However, these mechanisms are not considered in this study. AMPK, 5′ AMP-activated protein kinase; Ang II, angiotensin II; CD38, cADP-ribosesynthases; DOX, doxorubicin; eNOS, Endothelial NOS; Forkhead box protein O1; IDPs, intercalated disc proteins; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; p38 MAPK, p38 mitogen-activated protein kinases; p53, tumor protein P53; PARPs, poly-ADP-ribose polymerases; ROS, reactive oxygen species; SIRT, silent information regulator 2 (Sir2); TGF-β, transforming growth factor beta; FOXO1.
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References

    1. Adhikari A., Asdaq S. M. B., Al Hawaj M. A., Chakraborty M., Thapa G., Bhuyan N. R., et al. (2021). Anticancer drug-induced cardiotoxicity: Insights and pharmacogenetics. Pharmaceuticals 14, 970–1023. 10.3390/ph14100970 - DOI - PMC - PubMed
    1. Aktary Z., Alaee M., Pasdar M. (2017). Beyond cell-cell adhesion: Plakoglobin and the regulation of tumorigenesis and metastasis. Oncotarget 8, 32270–32291. 10.18632/oncotarget.15650 - DOI - PMC - PubMed
    1. Al-Amoudi A., Frangakis A. S. (2008). Structural studies on desmosomes. Biochem. Soc. Trans. 36, 181–187. 10.1042/BST0360181 - DOI - PubMed
    1. Alcendor R. R., Gao S., Zhai P., Zablocki D., Holle E., Yu X., et al. (2007). Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ. Res. 100, 1512–1521. 10.1161/01.RES.0000267723.65696.4a - DOI - PubMed
    1. Ando K., Uemura K., Kuzuya A., Maesako M., Asada-Utsugi M., Kubota M., et al. (2011). N-cadherin regulates p38 MAPK signaling via association with JNK-associated leucine zipper protein: Implications for neurodegeneration in Alzheimer disease. J. Biol. Chem. 286, 7619–7628. 10.1074/jbc.M110.158477 - DOI - PMC - PubMed

Grants and funding

The study has been supported by the grant from the Ministry of Science and Higher Education of the Russian Federation (agreement 075-15-2020-800).