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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 (15 November 2022) | Viewed by 21992

Special Issue Editors

Dr. Susan Currie

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals
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.

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

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Keywords

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

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Published Papers (6 papers)

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Research

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17 pages, 2737 KiB  
Article
Early Doxorubicin Myocardial Injury: Inflammatory, Oxidative Stress, and Apoptotic Role of Galectin-3
by Suhail Al-Salam, Karthishwaran Kandhan, Manjusha Sudhadevi, Javed Yasin and Saeed Tariq
Int. J. Mol. Sci. 2022, 23(20), 12479; https://doi.org/10.3390/ijms232012479 - 18 Oct 2022
Cited by 8 | Viewed by 2256
Abstract
Doxorubicin (DOXO) is an effective drug that is used in the treatment of a large number of cancers. Regardless of its important chemotherapeutic characteristics, its usage is restricted because of its serious side effects; the most obvious is cardiotoxicity, which can manifest acutely [...] Read more.
Doxorubicin (DOXO) is an effective drug that is used in the treatment of a large number of cancers. Regardless of its important chemotherapeutic characteristics, its usage is restricted because of its serious side effects; the most obvious is cardiotoxicity, which can manifest acutely or years after completion of treatment, leading to left ventricular dysfunction, dilated cardiomyopathy, and heart failure. Galectin 3 (Gal-3) is a beta galactoside binding lectin that has different roles in normal and pathophysiological conditions. Gal-3 was found to be upregulated in animal models, correlating with heart failure, atherosclerosis, and myocardial infarction. Male C57B6/J and B6.Cg-Lgals3 <tm 1 Poi>/J Gal-3 knockout (KO) mice were used for a mouse model of acute DOXO-induced cardiotoxicity. Mice were given DOXO or vehicle (normal saline), after which the mice again had free access to food and water. Heart and plasma samples were collected 5 days after DOXO administration and were used for tissue processing, staining, electron microscopy, and enzyme-linked immunosorbent assay (ELISA). There was a significant increase in the heart concentration of Gal-3 in Gal-3 wild type DOXO-treated mice when compared with the sham control. There were significantly higher concentrations of heart cleaved caspase-3, plasma troponin I, plasma lactate dehydrogenase, and plasma creatine kinase in Gal-3 KO DOXO-treated mice than in Gal-3 wild type DOXO-treated mice. Moreover, there were significantly higher heart antioxidant proteins and lower oxidative stress in Gal-3 wild type DOXO-treated mice than in Gal-3 KO DOXO-treated mice. In conclusion, Gal-3 can affect the redox pathways and regulate cell survival and death of the myocardium following acute DOXO injury. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Dysfunction and Implications in Anti-cancer Drug-Induced Cardiotoxicity)
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17 pages, 2729 KiB  
Article
Imatinib Mesylate Induces Necroptotic Cell Death and Impairs Autophagic Flux in Human Cardiac Progenitor Cells
by Robert Walmsley, Derek S. Steele, Georgina M. Ellison-Hughes, Sotiris Papaspyros and Andrew J. Smith
Int. J. Mol. Sci. 2022, 23(19), 11812; https://doi.org/10.3390/ijms231911812 - 5 Oct 2022
Cited by 2 | Viewed by 2236
Abstract
The receptor tyrosine kinase inhibitor imatinib improves patient cancer survival but is linked to cardiotoxicity. This study investigated imatinib’s effects on cell viability, apoptosis, autophagy, and necroptosis in human cardiac progenitor cells in vitro. Imatinib reduced cell viability (75.9 ± 2.7% vs. 100.0 [...] Read more.
The receptor tyrosine kinase inhibitor imatinib improves patient cancer survival but is linked to cardiotoxicity. This study investigated imatinib’s effects on cell viability, apoptosis, autophagy, and necroptosis in human cardiac progenitor cells in vitro. Imatinib reduced cell viability (75.9 ± 2.7% vs. 100.0 ± 0.0%) at concentrations comparable to peak plasma levels (10 µM). Imatinib reduced cells’ TMRM fluorescence (74.6 ± 6.5% vs. 100.0 ± 0.0%), consistent with mitochondrial depolarisation. Imatinib increased lysosome and autophagosome content as indicated by LAMP2 expression (2.4 ± 0.3-fold) and acridine orange fluorescence (46.0 ± 5.4% vs. 9.0 ± 3.0), respectively. Although imatinib increased expression of autophagy-associated proteins and also impaired autophagic flux, shown by proximity ligation assay staining for LAMP2 and LC3II (autophagosome marker): 48 h of imatinib treatment reduced visible puncta to 2.7 ± 0.7/cell from 11.3 ± 2.1 puncta/cell in the control. Cell viability was partially recovered by autophagosome inhibition by wortmannin, with the viability increasing 91.8 ± 8.2% after imatinib-wortmannin co-treatment (84 ± 1.5% after imatinib). Imatinib-induced necroptosis was associated with an 8.5 ± 2.5-fold increase in mixed lineage kinase domain-like pseudokinase activation. Imatinib-induced toxicity was rescued by RIP1 inhibition: 88.6 ± 3.0% vs. 100.0 ± 0.0% in the control. Imatinib applied to human cardiac progenitor cells depolarises mitochondria and induces cell death through necroptosis, recoverable by RIP1 inhibition, with a partial role for autophagy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Dysfunction and Implications in Anti-cancer Drug-Induced Cardiotoxicity)
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36 pages, 9507 KiB  
Article
Prophylactic Evidence of MSCs-Derived Exosomes in Doxorubicin/Trastuzumab-Induced Cardiotoxicity: Beyond Mechanistic Target of NRG-1/Erb Signaling Pathway
by Nesrine Ebrahim, Hajir A. Al Saihati, Ola Mostafa, Amira Hassouna, Sameh Abdulsamea, Eman Abd El Aziz M. El Gebaly, Nashwa Hassan Abo-Rayah, Dina Sabry, Mohamed El-Sherbiny, Abdelmonem G. Madboly, Noha Ibrahim Hussien, Raja El Hasnaoui Saadani, Hasnaa Ali Ebrahim, Omnia A. M. Badr, Nehal M. Elsherbiny and Rabab F. Salim
Int. J. Mol. Sci. 2022, 23(11), 5967; https://doi.org/10.3390/ijms23115967 - 25 May 2022
Cited by 11 | Viewed by 4209
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
(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Dysfunction and Implications in Anti-cancer Drug-Induced Cardiotoxicity)
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14 pages, 781 KiB  
Article
Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation
by Jun H. Heo, Sang R. Lee, Seong Lae Jo, Hyun Yang, Hye Won Lee and Eui-Ju Hong
Int. J. Mol. Sci. 2022, 23(1), 547; https://doi.org/10.3390/ijms23010547 - 4 Jan 2022
Cited by 2 | Viewed by 5068
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
(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Dysfunction and Implications in Anti-cancer Drug-Induced Cardiotoxicity)
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Review

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33 pages, 1038 KiB  
Review
Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review
by Bianca Saveria Fioretto, Irene Rosa, Marco Matucci-Cerinic, Eloisa Romano and Mirko Manetti
Int. J. Mol. Sci. 2023, 24(4), 4097; https://doi.org/10.3390/ijms24044097 - 17 Feb 2023
Cited by 4 | Viewed by 2763
Abstract
Systemic sclerosis (SSc, scleroderma) is a multifaceted rare connective tissue disease whose pathogenesis is dominated by immune dysregulation, small vessel vasculopathy, impaired angiogenesis, and both cutaneous and visceral fibrosis. Microvascular impairment represents the initial event of the disease, preceding fibrosis by months or [...] Read more.
Systemic sclerosis (SSc, scleroderma) is a multifaceted rare connective tissue disease whose pathogenesis is dominated by immune dysregulation, small vessel vasculopathy, impaired angiogenesis, and both cutaneous and visceral fibrosis. Microvascular impairment represents the initial event of the disease, preceding fibrosis by months or years and accounting for the main disabling and/or life-threatening clinical manifestations, including telangiectasias, pitting scars, periungual microvascular abnormalities (e.g., giant capillaries, hemorrhages, avascular areas, ramified/bushy capillaries) clinically detectable by nailfold videocapillaroscopy, ischemic digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. Despite a variety of available treatment options, treatment of SSc-related vascular disease remains problematic, even considering SSc etherogenity and the quite narrow therapeutic window. In this context, plenty of studies have highlighted the great usefulness in clinical practice of vascular biomarkers allowing clinicians to assess the evolution of the pathological process affecting the vessels, as well as to predict the prognosis and the response to therapy. The current narrative review provides an up-to-date overview of the main candidate vascular biomarkers that have been proposed for SSc, focusing on their main reported associations with characteristic clinical vascular features of the disease. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Dysfunction and Implications in Anti-cancer Drug-Induced Cardiotoxicity)
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19 pages, 1002 KiB  
Review
Cancer Therapy-Induced Cardiotoxicity—A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy
by Anurag Choksey and Kerstin N. Timm
Int. J. Mol. Sci. 2022, 23(1), 441; https://doi.org/10.3390/ijms23010441 - 31 Dec 2021
Cited by 28 | Viewed by 4415
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
(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Dysfunction and Implications in Anti-cancer Drug-Induced Cardiotoxicity)
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