Evaluation of Senescence and Its Prevention in Doxorubicin-Induced Cardiotoxicity Using Dynamic Engineered Heart Tissues

Linders, Annet N.; Dias, Itamar; Ovchinnikova, Ekaterina S.; Vermeer, Marloes; Hoes, Martijn F.; Mavrogenis, Georgios; Deiman, Frederik E; Gomez, Karla F. Arevalo; Bliley, Jacqueline M.; Nehme, Jamil; Vink, Aryan; Gietema, Jourik A.; Boer, Rudolf A. de; Westenbrink, B. Daan; Silljé, Herman H W; Hilfiker‐Kleiner, Denise; Laake, Linda W. van; Feinberg, Adam W.; Demaria, Marco; Meer, Peter van der

doi:10.1016/j.jaccao.2023.03.012

Cited by 8 publications

(2 citation statements)

References 32 publications

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“…Genetic ablation of p16 in cardiomyocytes also decreases the number of senescent cardiomyocytes, improves cardiac function, and decreases fibrosis five weeks after ischemia/reperfusion [11] . Doxorubicin (Dox) treatment increases myosin heavy chain-positive (MHC + )/p16 INK4a -positive (p16 + ) cells in the rat left ventricle [22] , suggesting that Dox induces cardiomyocyte senescence. Elimination of senescent cells improves cardiac function in the mouse model of Dox-induced cardiomyopathy [13] , although whether this is applicable in humans requires further investigation [23] .…”

Section: The Detrimental Effects Of Senescent Cardiomyocytes In the H...mentioning

confidence: 99%

Cardiomyocyte senescence and the potential therapeutic role of senolytics in the heart

Zhai,

Sadoshima

2024

J Cardiovasc Aging

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Cellular senescence in cardiomyocytes, characterized by cell cycle arrest, resistance to apoptosis, and the senescence-associated secretory phenotype, occurs during aging and in response to various stresses, such as hypoxia/reoxygenation, ischemia/reperfusion, myocardial infarction (MI), pressure overload, doxorubicin treatment, angiotensin II, diabetes, and thoracic irradiation. Senescence in the heart has both beneficial and detrimental effects. Premature senescence of myofibroblasts has salutary effects during MI and pressure overload. On the other hand, persistent activation of senescence in cardiomyocytes precipitates cardiac dysfunction and adverse remodeling through paracrine mechanisms during MI, myocardial ischemia/reperfusion, aging, and doxorubicin-induced cardiomyopathy. Given the adverse roles of senescence in many conditions, specific removal of senescent cells, i.e., senolysis, is of great interest. Senolysis can be achieved using senolytic drugs (such as Navitoclax, Dasatinib, and Quercetin), pharmacogenetic approaches (including INK-ATTAC and AP20187, p16-3MR and Ganciclovir, p16 ablation, and p16-LOX-ATTAC and Cre), and immunogenetic interventions (CAR T cells or senolytic vaccination). In order to enhance the specificity and decrease the off-target effects of senolytic approaches, investigation into the mechanisms through which cardiomyocytes develop and/or maintain the senescent state is needed.

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Section: The Detrimental Effects Of Senescent Cardiomyocytes In the H...mentioning

confidence: 99%

Cardiomyocyte senescence and the potential therapeutic role of senolytics in the heart

Zhai,

Sadoshima

2024

J Cardiovasc Aging

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“…In vivo studies in rodents have shown that doxorubicin can induce biomarkers of senescence in the myocardium of mice ( 123 ) and rats ( 124 ). Analysis of LV human heart tissue from patients with doxorubicin-induced cardiotoxicity has revealed increased expression of a range of markers of senescence in cardiomyocytes compared to LV tissue from healthy donors ( 125 ). In addition to cardiomyocytes, doxorubicin-induced senescence can potentially occur in cardiac fibroblasts and cardiac endothelial cells ( 126 ).…”

Section: Cardiotoxicitymentioning

confidence: 99%

Anticancer drugs and cardiotoxicity: the role of cardiomyocyte and non-cardiomyocyte cells

Koukorava,

Ahmed,

Almaghrabi

et al. 2024

Front. Cardiovasc. Med.

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Cardiotoxicity can be defined as “chemically induced heart disease”, which can occur with many different drug classes treating a range of diseases. It is the primary cause of drug attrition during pre-clinical development and withdrawal from the market. Drug induced cardiovascular toxicity can result from both functional effects with alteration of the contractile and electrical regulation in the heart and structural changes with morphological changes to cardiomyocytes and other cardiac cells. These adverse effects result in conditions such as arrhythmia or a more serious reduction in left ventricular ejection fraction (LVEF), which can lead to heart failure and death. Anticancer drugs can adversely affect cardiomyocyte function as well as cardiac fibroblasts and cardiac endothelial cells, interfering in autocrine and paracrine signalling between these cell types and ultimately altering cardiac cellular homeostasis. This review aims to highlight potential toxicity mechanisms involving cardiomyocytes and non-cardiomyocyte cells by first introducing the physiological roles of these cells within the myocardium and secondly, identifying the physiological pathways perturbed by anticancer drugs in these cells.

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Sex-related differences in delayed doxorubicin-induced cardiac dysfunction in C57BL/6 mice

Abdelgawad,

George,

Grant

et al. 2024

Arch Toxicol

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Evaluation of Senescence and Its Prevention in Doxorubicin-Induced Cardiotoxicity Using Dynamic Engineered Heart Tissues

Cited by 8 publications

References 32 publications

Cardiomyocyte senescence and the potential therapeutic role of senolytics in the heart

Cardiomyocyte senescence and the potential therapeutic role of senolytics in the heart

Anticancer drugs and cardiotoxicity: the role of cardiomyocyte and non-cardiomyocyte cells

Sex-related differences in delayed doxorubicin-induced cardiac dysfunction in C57BL/6 mice

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