New Insight Into Cardioprotection From Anthracyclines: Still Converging on the Mitochondria.
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ABSTRACT:
SUBMITTER: Chen Q
PROVIDER: S-EPMC10308034 | biostudies-literature | 2023 Jun
REPOSITORIES: biostudies-literature
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New Insight Into Cardioprotection From Anthracyclines: Still Converging on the Mitochondria.
Chen Qun Q Meléndez Giselle C GC Lesnefsky Edward J EJ
JACC. CardioOncology 20230620 3
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Project description:We have previously shown that transplantation of autologously derived, respiration-competent mitochondria by direct injection into the heart following transient ischemia and reperfusion enhances cell viability and contractile function. To increase the therapeutic potential of this approach, we investigated whether exogenous mitochondria can be effectively delivered through the coronary vasculature to protect the ischemic myocardium and studied the fate of these transplanted organelles in the heart. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and then reperfused for 10 minutes. Mitochondria were labeled with 18F-rhodamine 6G and iron oxide nanoparticles. The labeled mitochondria were either directly injected into the ischemic region or delivered by vascular perfusion through the coronary arteries at the onset of reperfusion. These hearts were used for positron emission tomography, microcomputed tomography, and magnetic resonance imaging with subsequent microscopic analyses of tissue sections to confirm the uptake and distribution of exogenous mitochondria. Injected mitochondria were localized near the site of delivery; while, vascular perfusion of mitochondria resulted in rapid and extensive dispersal throughout the heart. Both injected and perfused mitochondria were observed in interstitial spaces and were associated with blood vessels and cardiomyocytes. To determine the efficacy of vascular perfusion of mitochondria, an additional group of rabbit hearts were subjected to 30 minutes of regional ischemia and reperfused for 120 minutes. Immediately following regional ischemia, the hearts received unlabeled, autologous mitochondria delivered through the coronary arteries. Autologous mitochondria perfused through the coronary vasculature significantly decreased infarct size and significantly enhanced post-ischemic myocardial function. In conclusion, the delivery of mitochondria through the coronary arteries resulted in their rapid integration and widespread distribution throughout the heart and provided cardioprotection from ischemia-reperfusion injury.
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Project description:With the increasing age of the general population, medical conditions necessitating a surgical intervention will increase. Concomitant with advanced age, the prevalence of type 2 diabetes mellitus will also increase. These patients have a two- to three-fold higher risk of occurrence of cardiovascular events and are at higher risk of perioperative myocardial ischemia. This review will discuss recent advances in the field of perioperative cardioprotection and focus specifically on strategies that have aimed to protect the diabetic and the aged myocardium. This review will not deal with potential putative cardioprotective effects of opioids and anesthetic agents, as this is a very broad area that would necessitate a dedicated overview.
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Project description:The urocortin (UCN) hormones UCN1 and UCN2 have been shown previously to confer significant protection against myocardial ischaemia/reperfusion (I/R) injury; however, the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of UCNs that underpins their cardioprotective activity, a microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of UCN1 or UCN2 before the onset of reperfusion resulted in the differential regulation of 66 and 141 genes respectively, the majority of which have not been described previously. Functional analysis demonstrated that UCN-regulated genes are involved in a wide range of biological responses, including cell death (e.g. X-linked inhibitor of apoptosis protein), oxidative stress (e.g. nuclear factor erythroid derived 2-related factor 1/nuclear factor erythroid derived 2-like 1) and metabolism (e.g. Prkaa2/AMPK). In addition, both UCN1 and UCN2 were found to modulate the expression of a host of genes involved in G-protein-coupled receptor (GPCR) signalling including Rac2, Gnb1, Dab2ip (AIP1), Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of CRH receptors. Moreover, several of these GPCR-related genes have been shown previously to be involved in mitogen-activated protein kinase (MAPK) activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we have shown that both UCN1 and UCN2 significantly reduce free radical damage following myocardial infarction, and comparison of the UCN gene signatures with that of the anti-oxidant tempol revealed a significant overlap. These data uncover novel gene expression changes induced by UCNs, which will serve as a platform to further understand their mechanism of action in normal physiology and cardioprotection.
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Project description:α-Bisabolol (BSB) is a plant-derived sesquiterpene alcohol able to trigger regulated cell death in transformed cells, while deprived of the general toxicity in several mouse models. Here, we investigated the involvement of lysosomal and mitochondrial compartments in the cytotoxic effects of BSB, with a specific focus on the BH3-only activator protein BID. We found that BSB particularly accumulated in cancer cell lines, displaying a higher amount of lipid rafts as compared to normal blood cells. By means of western blotting and microscopy techniques, we documented rapid BSB-induced BID translocation to lysosomes and mitochondria, both of them becoming dysfunctional. Lysosomal membranes were permeabilized, thus blocking the cytoprotective autophagic flux and provoking cathepsin B leakage into the cytosol. Multiple flow cytometry-based experiments demonstrated the loss of mitochondrial membrane potential due to pore formation across the lipid bilayer. These parallel events converged on neoplastic cell death, an outcome significantly prevented by BID knockdown. Therefore, BSB promoted BID redistribution to the cell death executioner organelles, which in turn activated anti-autophagic and proapoptotic mechanisms. This is an example of how xenohormesis can be exploited to modulate basic cellular programs in cancer.
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Project description:The standard therapeutic approaches for acute myeloid leukemia (AML) continue to be based on anthracyclines and cytarabine. However, the prognosis for AML remains poor, especially for patients with high-risk disease. During the past decade, promising novel agents that target DNA replication and repair, as well as cell cycling and apoptosis, have been developed and are being actively investigated in AML. Among these agents is flavopiridol, which interferes with key steps of the cell cycle and effectively promotes cell death, and voreloxin, an intercalating agent that also targets topoisomerase II. Also under clinical study in AML are oligonucleotide antisense constructs, which suppress the translation of proteins essential for leukemic blast survival and proliferation, and agents that target antiapoptotic cascades. In summary, it is hoped that novel therapies such as these will augment and/or supplant our current cytarabine- and anthracycline-based approaches, overcome active drug-resistance pathways, and eventually improve outcomes for patients with AML.
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Project description:RationaleMitochondria are key organelles involved in cell survival and death during the acute phenomena of myocardial ischemia-reperfusion (i.e., myocardial infarction). To investigate the functions of isolated mitochondria such as calcium retention capacity, oxidative phosphorylation, and reactive oxygen species (ROS) production, already established methods are based on extramitochondrial measurements of the whole mitochondria population.ObjectiveThe aim of this study was to develop a reliable and well-characterized method for multiparametric analysis of isolated single mitochondrion by flow cytometry (FC) in the context of myocardial infarction. The advantage of FC is the possibility to give a simultaneous analysis of morphological parameters (side and forward scatters: SSC and FSC) for each mitochondrion, combined with intramitochondrial measurements of several biological markers, such as ROS production or membrane potential (Δφm), using specific fluorescent probes.Methods and resultsFor this study, a rat model of ischemia-reperfusion and a protective approach of post-conditioning using low reperfusion pressure was used. Thanks to the use of specific probes (NAO, MTR, TMRM, DilC1, and DHR123) combined with flow cytometry, we propose a method: (i) to identify mitochondrial populations of interest based on quality criteria (NAO/TMRM double staining); (ii) to monitor their morphological criteria, especially during swelling due to calcium overload; and (iii) to compare mitochondrial functions (membrane potential and ROS production) in different experimental groups. Applied to mitochondria from ischemic hearts, these measurements revealed that individual mitochondria are altered and that cardioprotection by low-pressure reperfusion reduces damage, as expected.ConclusionsOur results highlight FC as a reliable and sensitive method to investigate changes in mitochondrial functions and morphology in pathological conditions that disrupts their activity such as the case in ischemia-reperfusion. This methodological approach can be extended to other pathologies involving mitochondrial dysfunctions. Moreover, FC offers the possibility to work with very small amounts of isolated mitochondria, a factor that may limit the use of classical methods.
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Project description:Among the enzymes involved in NAD homeostasis, nicotinamide mononucleotide adenylyltransferases (NMNAT1-3) are central to intracellular NAD formation. Although NMNAT3 is postulated to be a mitochondrial enzyme contributing to NAD-dependent organelle functioning, information on endogenous proteins is lacking. We report that in human cells a single gene nmnat3 localized on chromosome 3 codes for two mRNA splice variants NMNATv1 and FKSG76, whereas the previously reported NMNAT3v2 transcript is not present. However, NMNAT3v1 and FKSG76 proteins are not detectable, consistent with the finding that an upstream ORF in their mRNAs negatively regulates translation. NMNAT3v1 transfection demonstrates that the protein is cytosolic and inactive, whereas FKSG76 is mitochondrial but operates NAD cleavage rather than synthesis. In keeping with the lack of NMNAT3, we show that extracellular NAD, but not its metabolic precursors, sustains mitochondrial NAD pool in an ATP-independent manner. Data of the present study modify the scenario of the origin of mitochondrial NAD by showing that, in human cells, NMNAT3 is absent in mitochondria, and, akin to plants and yeast, cytosolic NAD maintains the mitochondrial NAD pool.
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Project description:Rationale: Ischemic heart disease remains a primary threat to human health, while its precise etiopathogenesis is still unclear. TBC domain family member 15 (TBC1D15) is a RAB7 GTPase-activating protein participating in the regulation of mitochondrial dynamics. This study was designed to explore the role of TBC1D15 in acute myocardial infarction (MI)-induced cardiac injury and the possible mechanism(s) involved. Methods: Mitochondria-lysosome interaction was evaluated using transmission electron microscopy and live cell time-lapse imaging. Mitophagy flux was measured by fluorescence and western blotting. Adult mice were transfected with adenoviral TBC1D15 through intra-myocardium injection prior to a 3-day MI procedure. Cardiac morphology and function were evaluated at the levels of whole-heart, cardiomyocytes, intracellular organelles and cell signaling transduction. Results: Our results revealed downregulated level of TBC1D15, reduced systolic function, overt infarct area and myocardial interstitial fibrosis, elevated cardiomyocyte apoptosis and mitochondrial damage 3 days after MI. Overexpression of TBC1D15 restored cardiac systolic function, alleviated infarct area and myocardial interstitial fibrosis, reduced cardiomyocyte apoptosis and mitochondrial damage although TBC1D15 itself did not exert any myocardial effect in the absence of MI. Further examination revealed that 3-day MI-induced accumulation of damaged mitochondria was associated with blockade of mitochondrial clearance because of enlarged defective lysosomes and subsequent interrupted mitophagy flux, which were attenuated by TBC1D15 overexpression. Mechanistic studies showed that 3-day MI provoked abnormal mitochondria-lysosome contacts, leading to lysosomal enlargement and subsequently disabled lysosomal clearance of damaged mitochondria. TBC1D15 loosened the abnormal mitochondria-lysosome contacts through both the Fis1 binding and the RAB7 GAPase-activating domain of TBC1D15, as TBC1D15-dependent beneficial responses were reversed by interference with either of these two domains both in vitro and in vivo. Conclusions: Our findings indicated a pivotal role of TBC1D15 in acute MI-induced cardiac anomalies through Fis1/RAB7 regulated mitochondria-lysosome contacts and subsequent lysosome-dependent mitophagy flux activation, which may provide a new target in the clinical treatment of acute MI.
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Project description:Cardiotoxicity is a feared side effect that may limit the clinical use of anthracyclines. It may indeed affect the quality of life and survival of patients with cancer, regardless of oncological prognosis. This paper provides an overview of anthracycline-induced cardiotoxicity in terms of definition, classification, incidence, risk factors, possible mechanisms, diagnosis, and treatment. We also report effective strategies for preventing cardiotoxicity. In addition, we discuss limiting current approaches, the need for a new classification, and early cardiotoxicity detection and treatment. Probably, anthracycline-induced cardiotoxicity is a continuous phenomenon that starts from myocardial cell injury; it is followed by left ventricular ejection fraction (LVEF) and, if not diagnosed and cured early, progressively leads to symptomatic heart failure. Anthracycline-induced cardiotoxicity can be detected at a preclinical phase. The role of biomarkers, in particular troponins, in identifying subclinical cardiotoxicity and its therapy with angiotensin-converting enzyme inhibitors (mainly enalapril) to prevent LVEF reduction is a recognized and effective strategy. If cardiac dysfunction has already occurred, partial or complete LVEF recovery may still be obtained in case of early detection of cardiotoxicity and prompt heart failure treatment.
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Project description:Introduction:CoenzymeQ10 (CoQ10) is a well-known antioxidant and anti-inflammatory agent with cardioprotective properties. However, clinical trials based on its oral administration have failed to provide significant effect on cardiac functionality. The main limitation of CoQ10 is based on its very low oral bioavailability and instability that limit dramatically its effects as a cardioprotective agent. Herein, we loaded CoQ10 in high bioavailable nano-emulsions (NEs) coated with chitosan or chitosan and hyaluronic acid in order to improve its performance. Methods:We tested cardioprotective and hepatoprotective effects of CoQ10-loaded nano-carriers against Doxorubicin and Trastuzumab toxicities in cardiomyocytes and liver cells through analysis of cell viability, lipid peroxidation, expression of leukotrienes, p65/NF-kB and pro-inflammatory cytokines involved in anticancer-induced cardio and hepatotoxicity. Results:Nano-carriers showed high stability and loading ability and increased cell viability both in hepatocytes and cardiomyocytes during anticancer treatments. We observed that these effects are mediated by the inhibition of lipid peroxidation and reduction of the inflammation. CoQ10-loaded nano-emulsions showed also strong anti-inflammatory effects reducing leukotriene B4 and p65/NF-?B expression and Interleukin 1? and 6 production during anticancer treatments. Discussion:Anthracyclines and Human epidermal growth factor receptor (HER2) inhibitors have shown significant anticancer effects in clinical practice but their use is characterized by cardiotoxicity and hepatotoxicity. Nano-carriers loaded with CoQ10 showed cardio and hepatoprotective properties mediated by reduction of oxidative damages and pro-inflammatory mediators. These results set the stage for preclinical studies of cardio and hepatoprotection in HER2+ breast cancer-bearing mice treated with Doxorubicin and Trastuzumab.
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