MicroRNAs in the diagnosis and prevention of drug-induced cardiotoxicity

Skála, Martin; Hanousková, Barbora; Skálová, Lenka; Matoušková, Petra

doi:10.1007/s00204-018-2356-z

Cited by 38 publications

(28 citation statements)

References 69 publications

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“…51 Circulating miRNAs were also used as biomarkers in drug safety assessment because of their tissue specificity and early release in plasma after tissue injury. Several studies reported the association of specific circulating miRNAs and cardiotoxicity, 47 hepatotoxicity, 52 and, nephrotoxicity. 53,54 In this review, we have summarized the studies reporting miR-NAs that are associated with AIC using in vivo and in vitro approaches (Table 2, Figure 3).…”

Section: Epigenetics and Aicmentioning

confidence: 99%

Epigenetic Changes Associated With Anthracycline‐Induced Cardiotoxicity

Tantawy

Pamittan

Singh

et al. 2020

Clinical Translational Sci

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Advances in cancer treatment have significantly improved the survival of patients with cancer, but, unfortunately, many of these treatments also have long‐term complications. Cancer treatment‐related cardiotoxicities are becoming a significant clinical problem that a new discipline, Cardio‐Oncology, was established to advance the cardiovascular care of patients with growing cancer populations. Anthracyclines are a class of chemotherapeutic agents used to treat many cancers in adults and children. Their clinical use is limited by anthracycline‐induced cardiotoxicity (AIC), which can lead to heart failure. Early‐onset cardiotoxicity appears within a year of treatment, whereas late‐onset cardiotoxicity occurs > 1 year and even up to decades after treatment completion. The pathophysiology of AIC was hypothesized to be caused by generation of reactive oxygen species that lead to lipid peroxidation, defective mitochondrial biogenesis, and DNA damage of the cardiomyocytes. The accumulation of anthracycline metabolites was also proposed to cause mitochondrial damage and the induction of cardiac cell apoptosis, which induces arrhythmias, contractile dysfunction, and cardiomyocyte death. This paper will provide a general overview of cardiotoxicity focusing on the effect of anthracyclines and their epigenetic molecular mechanisms on cardiotoxicity.

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Section: Epigenetics and Aicmentioning

confidence: 99%

Epigenetic Changes Associated With Anthracycline‐Induced Cardiotoxicity

Tantawy

Pamittan

Singh

et al. 2020

Clinical Translational Sci

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“…A fine manipulation of miRNA expression and function through systemic or local delivery of miRNA inhibitors (antimiRs) or mimics, has triggered the interest for miRNAs as innovative therapeutic targets 8 , 9 . MiRNAs are emerging as a novel treatment for cardiovascular diseases 9 – 11 and recently, several studies have investigated the role of miRNAs in DOXO-induced cardiotoxicity 12 , 13 . MiR-34a is involved in several cellular processes, such as apoptosis, senescence and energy metabolism 14 , 15 and is recognized as a key regulator in cardiac diseases and repair 16 – 20 .…”

Section: Introductionmentioning

confidence: 99%

Cardioprotective effects of miR-34a silencing in a rat model of doxorubicin toxicity

Piegari

Cozzolino

Ciuffreda

et al. 2020

Sci Rep

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Cardiotoxicity remains a serious problem in anthracycline-treated oncologic patients. Therapeutic modulation of microRNA expression is emerging as a cardioprotective approach in several cardiovascular pathologies. MiR-34a increased in animals and patients exposed to anthracyclines and is involved in cardiac repair. In our previous study, we demonstrated beneficial effects of miR-34a silencing in rat cardiac cells exposed to doxorubicin (DOXO). The aim of the present work is to evaluate the potential cardioprotective properties of a specific antimiR-34a (Ant34a) in an experimental model of DOXO-induced cardiotoxicity. Results indicate that in our model systemic administration of Ant34a completely silences miR-34a myocardial expression and importantly attenuates DOXOinduced cardiac dysfunction. Ant34a systemic delivery in DOXO-treated rats triggers an upregulation of prosurvival miR-34a targets Bcl-2 and SIRT1 that mediate a reduction of DOXO-induced cardiac damage represented by myocardial apoptosis, senescence, fibrosis and inflammation. These findings suggest that miR-34a therapeutic inhibition may have clinical relevance to attenuate DOXO-induced toxicity in the heart of oncologic patients. The anthracycline doxorubicin (DOXO) is a very powerful antineoplastic drug whose clinical use is limited by cardiotoxicity, its main side effect that may occur both acutely and chronically, affecting the quality of life of otherwise successfully treated oncologic patients 1,2. Anthracycline cardiotoxicity begins with subclinical myocardial damage, progresses to an early asymptomatic deterioration in left ventricle (LV) ejection fraction (EF) and ends, if not properly treated, with a symptomatic and often intractable heart failure (HF). For what concerns myocardial function, diastolic dysfunction may represent a precocious manifestation of DOXO cardiotoxicity, associated with ventricular relaxation and chamber wall stiffness leading to an alteration of ventricular function that first involves diastole and then eventually affects systole 3-6. Given the growing successful of chemotherapy with the significant increase in cancer survival, the clinical significance of DOXO cardiotoxicity is by no means small 7. Therefore, there is a serious need of an efficacious cardioprotective strategy to prevent or reduce ventricular complications. MicroRNAs (miRNAs) are small noncoding RNAs that suppress protein expression through binding and silencing specific mRNAs. A single miRNA inhibits many different mRNAs simultaneously, thus allowing an amplification of biological responses. A fine manipulation of miRNA expression and function through systemic or local delivery of miRNA inhibitors (antimiRs) or mimics, has triggered the interest for miRNAs as innovative therapeutic targets 8,9. MiRNAs are emerging as a novel treatment for cardiovascular diseases 9-11 and recently, several studies have investigated the role of miRNAs in DOXO-induced cardiotoxicity 12,13. MiR-34a is involved in several cellular processes, such as apoptosis, senescence ...

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“…[17][18][19] Several miRNAs have been implicated in cardiotoxicity caused by anthracyclines. 20,21 For example, miR-21 prevents DOX-induced cardiomyocyte apoptosis by targeting BTG2, 22 while miR-208a mediates DOX-induced cardiotoxicity through regulating GATA4. 23 Additional in vitro and in vivo studies have implicated miR-532-3p, miR-34a-5p and miR-451 in DOX-induced cardiotoxicity.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐129‐1‐3p protects cardiomyocytes from pirarubicin‐induced apoptosis by down‐regulating the GRIN2D‐mediated Ca²⁺ signalling pathway

Qin

Tan

et al. 2020

J Cellular Molecular Medi

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Pirarubicin (THP), an anthracycline anticancer drug, is a first-line therapy for various solid tumours and haematologic malignancies. However, THP can cause dosedependent cumulative cardiac damage, which limits its therapeutic window. The mechanisms underlying THP cardiotoxicity are not fully understood. We previously showed that MiR-129-1-3p, a potential biomarker of cardiovascular disease, was down-regulated in a rat model of THP-induced cardiac injury. In this study, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses to determine the pathways affected by miR-129-1-3p expression. The results linked miR-129-1-3p to the Ca 2+ signalling pathway. TargetScan database screening identified a tentative miR-129-1-3p-binding site at the 3′-UTR of GRIN2D, a subunit of the N-methyl-D-aspartate receptor calcium channel. A luciferase reporter assay confirmed that miR-129-1-3p directly regulates GRIN2D. In H9C2 (rat) and HL-1 (mouse) cardiomyocytes, THP caused oxidative stress, calcium overload and apoptotic cell death. These THP-induced changes were ameliorated by miR-129-1-3p overexpression, but exacerbated by miR-129-1-3p knock-down. In addition, miR-129-1-3p overexpression in cardiomyocytes prevented THP-induced changes in the expression of proteins that are either key components of Ca 2+ signalling or important regulators of intracellular calcium trafficking/balance in cardiomyocytes including GRIN2D, CALM1, CaMKⅡδ, RyR2-pS2814, SERCA2a and NCX1.Together, these bioinformatics and cell-based experiments indicate that miR-129-1-3p protects against THP-induced cardiomyocyte apoptosis by down-regulating the GRIN2D-mediated Ca 2+ pathway. Our results reveal a novel mechanism underlying the pathogenesis of THP-induced cardiotoxicity. The miR-129-1-3p/Ca 2+ signalling pathway could serve as a target for the development of new cardioprotective agents to control THP-induced cardiotoxicity. K E Y W O R D Sapoptosis, Ca 2+ signalling pathway, cardiomyocytes, GRIN2D, miR-129-1-3p, pirarubicin | 2261 LI et aL.

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MicroRNAs in the diagnosis and prevention of drug-induced cardiotoxicity

Cited by 38 publications

References 69 publications

Epigenetic Changes Associated With Anthracycline‐Induced Cardiotoxicity

Epigenetic Changes Associated With Anthracycline‐Induced Cardiotoxicity

Cardioprotective effects of miR-34a silencing in a rat model of doxorubicin toxicity

MicroRNA‐129‐1‐3p protects cardiomyocytes from pirarubicin‐induced apoptosis by down‐regulating the GRIN2D‐mediated Ca²⁺ signalling pathway

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MicroRNAs in the diagnosis and prevention of drug-induced cardiotoxicity

Cited by 38 publications

References 69 publications

Epigenetic Changes Associated With Anthracycline‐Induced Cardiotoxicity

Epigenetic Changes Associated With Anthracycline‐Induced Cardiotoxicity

Cardioprotective effects of miR-34a silencing in a rat model of doxorubicin toxicity

MicroRNA‐129‐1‐3p protects cardiomyocytes from pirarubicin‐induced apoptosis by down‐regulating the GRIN2D‐mediated Ca2+ signalling pathway

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MicroRNA‐129‐1‐3p protects cardiomyocytes from pirarubicin‐induced apoptosis by down‐regulating the GRIN2D‐mediated Ca²⁺ signalling pathway