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Special Issue "Molecular Mechanisms of Cardiovascular Dysfunction and Implications in Anti-cancer Drug-Induced Cardiotoxicity"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 2949

Special Issue Editors

Prof. Dr. Susan Currie
E-Mail
Guest Editor
Strathclyde Institute of Pharmacy & Biomedical Sciences University of Strathclyde, Glasgow, UK
Interests: cardiovascular calcium handling in health and disease; in vivo models of cardiac hypertrophy and cardiotoxicity; cardiac fibroblasts: cardiomyocytes; vascular endothelial and smooth muscle cells in health and disease
Dr. Margaret Rose Cunningham
E-Mail Website
Co-Guest Editor
Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, Univesity of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, Scotland, UK
Interests: cardiovascular; GPCRs; cardiotoxicity; thrombin; thrombin receptors; receptor pharmacology; receptor dimerisation; protein-protein interactions; cell signalling

Special Issue Information

Dear Colleagues,

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the 21st century. An emerging concern in recent years has been the contribution that anti-cancer drug-induced cardiotoxicity adds to the global burden of CVD. A variety of anti-cancer treatments can cause damage to the heart, resulting in tissue remodelling, contractile dysfunction and, in extreme cases, heart failure. So far, the molecular mechanisms underlying these drug-induced effects in both contractile and non-contractile cells of the heart remain unclear. Some of the key mechanisms that could be affected by anti-cancer agents include calcium signalling, pro-inflammatory signalling, mitochondrial function and cell metabolism. This Special Issue of IJMS offers a platform for high-quality publications exploring novel molecular mechanisms underlying anti-cancer drug-induced cardiotoxicity across different cell types of the heart. This is with a view to highlighting cellular targets that could be important for safety pharmacology in drug design going forward.

Prof. Dr. Susan Currie
Guest Editor
Dr. Margaret Rose Cunningham
Co-Guest Editor

Manuscript Submission Information

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Keywords

  • heart disease
  • toxicity
  • anti-cancer drugs
  • remodelling
  • cell signalling
  • cardiac myocytes
  • cardiac fibroblasts

Published Papers (3 papers)

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Research

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Article
Prophylactic Evidence of MSCs-Derived Exosomes in Doxorubicin/Trastuzumab-Induced Cardiotoxicity: Beyond Mechanistic Target of NRG-1/Erb Signaling Pathway
Int. J. Mol. Sci. 2022, 23(11), 5967; https://doi.org/10.3390/ijms23115967 - 25 May 2022
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Abstract
Trastuzumab (Trz) is a humanized monoclonal antibody targeting epidermal growth factor receptor 2 (HER2; ErbB2). The combined administration of Trz and doxorubicin (DOX) has shown potent anti-cancer efficacy; however, this regimen may be accompanied by severe cardiac toxicity. Mesenchymal stem cells (MSCs)-derived exosomes [...] Read more.
Trastuzumab (Trz) is a humanized monoclonal antibody targeting epidermal growth factor receptor 2 (HER2; ErbB2). The combined administration of Trz and doxorubicin (DOX) has shown potent anti-cancer efficacy; however, this regimen may be accompanied by severe cardiac toxicity. Mesenchymal stem cells (MSCs)-derived exosomes are nanosized vesicles that play a crucial role in cell–cell communication and have shown efficacy in the treatment of various diseases. In this study, we aim to investigate the cardioprotective effects of MSCs-derived exosomes in a DOX/Trz- mediated cardiotoxicity model, and the possible mechanisms underlying these effects are elucidated. Forty-nine male rats were randomly assigned into four groups: Group I (control); Group II (Dox/Trz); Group III (protective group); and Group IV (curative group). Cardiac hemodynamic parameters, serum markers of cardiac injury, oxidative stress indices, and cardiac histopathology were investigated. Further, transcript profile of specific cardiac tissue injury markers, apoptotic markers, and fibrotic markers were analyzed using qRT-PCR, while the protein expressions of pAkt/Akt, pERK/ERK, pJNK/JNK, pJNK/JNK, and pSTAT3/STAT3 were evaluated by ELISA. Additionally, cardiac mirR-21 and miR-26a were assessed. A combined administration of DOX/Trz disrupted redox and Ca2+ homeostasis in cardiac tissue induced myocardial fibrosis and myofibril loss and triggered cardiac DNA damage and apoptosis. This cardiotoxicity was accompanied by decreased NRG-1 mRNA expression, HER2 protein expression, and suppressed AKT and ERK phosphorylation, while triggering JNK phosphorylation. Histological and ultra-structural examination of cardiac specimens revealed features typical of cardiac tissue injury. Moreover, a significant decline in cardiac function was observed through biochemical testing of serum cardiac markers and echocardiography. In contrast, the intraperitoneal administration of MSCs-derived exosomes alleviated cardiac injury in both protective and curative protocols; however, superior effects were observed in the protective protocol. The results of the current study indicate the ability of MSCs-derived exosomes to protect from and attenuate DOX/Trz-induced cardiotoxicity. The NRG-1/HER2, MAPK, PI3K/AKT, PJNK/JNK, and PSTAT/STAT signaling pathways play roles in mediating these effects. Full article
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Article
Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation
Int. J. Mol. Sci. 2022, 23(1), 547; https://doi.org/10.3390/ijms23010547 - 04 Jan 2022
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Abstract
Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has [...] Read more.
Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced β-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from β-oxidation to glycolysis, may induce cardiac structural remodeling. Full article
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Review

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Review
Cancer Therapy-Induced Cardiotoxicity—A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy
Int. J. Mol. Sci. 2022, 23(1), 441; https://doi.org/10.3390/ijms23010441 - 31 Dec 2021
Cited by 3 | Viewed by 909
Abstract
Long-term cardiovascular complications of cancer therapy are becoming ever more prevalent due to increased numbers of cancer survivors. Cancer therapy-induced cardiotoxicity (CTIC) is an incompletely understood consequence of various chemotherapies, targeted anti-cancer agents and radiation therapy. It is typically detected clinically by a [...] Read more.
Long-term cardiovascular complications of cancer therapy are becoming ever more prevalent due to increased numbers of cancer survivors. Cancer therapy-induced cardiotoxicity (CTIC) is an incompletely understood consequence of various chemotherapies, targeted anti-cancer agents and radiation therapy. It is typically detected clinically by a reduction in cardiac left ventricular ejection fraction, assessed by echocardiography. However, once cardiac functional decline is apparent, this indicates irreversible cardiac damage, highlighting a need for the development of diagnostics which can detect CTIC prior to the onset of functional decline. There is increasing evidence to suggest that pathological alterations to cardiac metabolism play a crucial role in the development of CTIC. This review discusses the metabolic alterations and mechanisms which occur in the development of CTIC, with a focus on doxorubicin, trastuzumab, imatinib, ponatinib, sunitinib and radiotherapy. Potential methods to diagnose and predict CTIC prior to functional cardiac decline in the clinic are evaluated, with a view to both biomarker and imaging-based approaches. Finally, the therapeutic potential of therapies which manipulate cardiac metabolism in the context of adjuvant cardioprotection against CTIC is examined. Together, an integrated view of the role of metabolism in pathogenesis, diagnosis and treatment is presented. Full article
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