Adiponectin通过FoxO1信号通路减轻阿霉素细胞毒性的作用机制研究

目的 阐明FoxO1在脂联素(Adiponectin,APN)减轻阿霉素(Doxorubicin,DOX)心肌细胞毒性中的作用及机制.方法 将分离的乳鼠心肌原代细胞(Neonatal rat cardiomyocytes,nrCMs)随机分为对照组(CON)、APN处理组(APN)、DOX损伤组(DOX)、APN保护组...     

Anthracycline Associated Disturbances of Cardiovascular Homeostasis

Despite the dynamic progress of modern medicine, oncological and cardiovascular diseases (CVD) remain a severe economic burden worldwide. Therefore, the study of chemotherapeutic cardiotoxicity appears to be comprehensively demanded. Nowadays, pharmacological therapy in oncology has undoubtedly unprecedented development, but at the same time, the rates of cardiovascular complications of chemotherapy still remain unchanged. The well-established and highly effective, but at the same time, cardiotoxic anthracyclines have not lost their relevance. Furthermore, they remain indispensable components of an immense amount of chemotherapy regimens, such as AC, FAC, etc. Moreover, the anthracycline-containing chemotherapy regimens have become a standard of care in several cancer types. In the context of the above mentioned, the study of the pathophysiological mechanisms, biochemical aspects, and dynamics of the morphological remodeling of doxorubicin-induced cardiovascular homeostasis disturbances will enable finding new targets of pharmacological therapy, which either in the short or long perspectives, will have a beneficial effect, improving both the quality of life and prognosis of oncological patients. This article covers a versatile overview of the molecular mechanisms of doxorubicin-induced cardiotoxicity. The pathogenesis of cardiotoxicity assessment could help to explore specific molecular mechanisms that initiate cardiovascular alteration that may favorably affect the future development of targeted drugs that could prevent cardiovascular events in cancer patients.     

Mitochondrial catastrophe during doxorubicin‐induced cardiotoxicity: a review of the protective role of melatonin

Anthracyclines, such as doxorubicin, are among the most valuable treatments for various cancers, but their clinical use is limited due to detrimental side effects such as cardiotoxicity. Doxorubicin‐induced cardiotoxicity is emerging as a critical issue among cancer survivors and is an area of much significance to the field of cardio‐oncology. Abnormalities in mitochondrial functions such as defects in the respiratory chain, decreased adenosine triphosphate production, mitochondrial DNA damage, modulation of mitochondrial sirtuin activity and free radical formation have all been suggested as the primary causative factors in the pathogenesis of doxorubicin‐induced cardiotoxicity. Melatonin is a potent antioxidant, is nontoxic, and has been shown to influence mitochondrial homeostasis and function. Although a number of studies support the mitochondrial protective role of melatonin, the exact mechanisms by which melatonin confers mitochondrial protection in the context of doxorubicin‐induced cardiotoxicity remain to be elucidated. This review focuses on the role of melatonin on doxorubicin‐induced bioenergetic failure, free radical generation, and cell death. A further aim is to highlight other mitochondrial parameters such as mitophagy, autophagy, mitochondrial fission and fusion, and mitochondrial sirtuin activity, which lack evidence to support the role of melatonin in the context of cardiotoxicity.     

Cardioprotective Effects of Hesperetin against Doxorubicin-Induced Oxidative Stress and DNA Damage in Rat

Doxorubicin is a widely used chemotherapeutic agent; however, its clinical uses are limited due to its cardiotoxicity associated with an induction of oxidative stress. This study was aimed to investigate the protective effect of hesperetin against doxorubicin-induced cardiotoxicity in rats. Doxorubicin was administered at the dosage of 4 mg/kg bw/week, ip for a period of 5 consecutive weeks. Hesperetin was administered at the dosages of 25, 50 and 100 mg/kg bw, po by gavage for 5 consecutive days in a week for 5 weeks. The animals were killed 1 week after the last injection of doxorubicin. Hesperetin at the doses of 50 and 100 mg/kg bw significantly reduced MDA and increased GSH levels in the doxorubicin-treated animals. Further, hesperetin significantly reduced doxorubicin-induced DNA damage as well as apoptosis at 25, 50, and 100 mg/kg bw as evident from the comet and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assays, respectively. Thus, hesperetin ameliorated doxorubicin-induced cardiotoxicity by reducing oxidative stress, abnormal cellular morphology and DNA damage in rat. Moreover, nuclear factor-kappa B, p38, and caspase-3 play a role in the hesperetin-mediated protection against doxorubicin-induced cardiotoxicity. This study indicates the protective effect of hesperetin against doxorubicin-induced cardiotoxicity.     

Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity

Doxorubicin is known to have cumulative dose-dependent cardiotoxicity, and a tumor suppressor protein p53 has been implicated in the pathogenesis of doxorubicin cardiotoxicity. However, how p53 is induced by doxorubicin and mediates the cardiotoxic effects of doxorubicin remains elusive. In cultured cardiac myocytes, doxorubicin induced oxidative stress, DNA damage, ATM activation, and p53 induction. A free radical scavenger NAC attenuated all of these events, whereas an ATM kinase inhibitor wortmannin attenuated doxorubicin-induced ATM activation and p53 induction but not oxidative stress. Doxorubicin treatment in vivo also induced oxidative stress, DNA damage, ATM activation, and p53 accumulation. These observations suggest that p53 induction by doxorubicin is mediated by oxidative DNA damage-ATM pathway. Doxorubicin-induced contractile dysfunction and myocyte apoptosis in vivo were attenuated in heterozygous p53 deficient mice and cardiac-restricted Bcl-2 transgenic mice, suggesting that myocyte apoptosis plays a central role downstream of p53 in doxorubicin cardiotoxicity. We also tested whether pitavastatin exerts protective effects on doxorubicin cardiotoxicity. Pitavastatin attenuated doxorubicin-induced oxidative stress, DNA damage, ATM activation, p53 accumulation, and apoptosis in vitro. Pitavastatin also attenuated myocyte apoptosis and contractile dysfunction in vivo. The beneficial effects of pitavastatin were reversed by intermediate products of the mevalonate pathway that are required for the activation of Rac1, and Rac1 inhibitor exhibited cardioprotective effects comparable to those of pitavastatin. These data collectively suggest that doxorubicin-induced cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway, and is attenuated by pitavastatin through its antioxidant effect involving Rac1 inhibition.     

Mechanisms and management of doxorubicin cardiotoxicity

Doxorubicin is an effective anti-tumor agent with a cumulative dose-dependent cardiotoxicity. In addition to its principal toxic mechanisms involving iron and redox reactions, recent studies have described new mechanisms of doxorubicin-induced cell death, including abnormal protein processing, hyper-activated innate immune responses, inhibition of neuregulin-1 (NRG1)/ErbB(HER) signalling, impaired progenitor cell renewal/cardiac repair, and decreased vasculogenesis. Although multiple mechanisms involved in doxorubicin cardiotoxicity have been studied, there is presently no clinically proven treatment established for doxorubicin cardiomyopathy. Iron chelator dexrazoxane, angiotensin converting enzyme (ACE) inhibitors, and β-blockade have been proposed as potential preventive strategies for doxorubicin cardiotoxicity. Novel approaches such as anti-miR-146 or recombinant NRG1 to increase cardiomyocyte resistance to toxicity may be of interest in the future.     

Antioxidant defense against anthracycline cardiotoxicity by metallothionein

Anthracycline cardiotoxicity is related to oxidative stress generated from the metabolism of anthracyclines in the heart. Studies using transgenic mice with high levels of antioxidants such as catalase or metallothionein (MT) specifically in the heart have demonstrated that elevation of cardiac antioxidant defense leads to intervention of anthracycline cardiotoxicity. MT protection against anthracycline-induced cardiac toxicity is related to its anti-apoptotic effect by inhibiting both p38-MAPK-mediated and mitochondrial cytochrome c-release-mediated apoptotic signaling. The anti-apoptotic effect of MT is closely related to its antioxidant action, which involves regulation of zinc homeostasis by the MT redox cycle. MT interferes with oxidant-mediated detrimental process through at least in part zinc release and zinc transfers directly from MT to acceptor proteins. In addition, MT posttranslationally modulates critical proteins involved in mitochondrial respiration and energy metabolism. All of these processes constitute the mechanisms by which MT protects from anthracycline cardiotoxicity.     

线粒体动力学和线粒体自噬与心血管疾病的研究进展

线粒体是一种动态的细胞器,通过响应各种代谢和环境的信号,分裂和融合改变其形态和结构,从而维持细胞的正常功能.它们短暂而快速的形态变化对于细胞周期、免疫、凋亡和线粒体质量控制等许多复杂的细胞过程至关重要.线粒体自噬与线粒体质量控制密切相关,通过将受损的功能障碍的线粒体转运到溶酶体进行降解,促进心肌细胞受损线粒体的更新,并...     

Protein Quality Control Dysfunction in Cardiovascular Complications Induced by Anti-Cancer Drugs

Cardiovascular complications, including heart failure, hypertension, ischemic syndromes and venous thromboembolism, have been identified in patients treated with anti-cancer drugs. Oxidative stress, mitochondrial dysfunction and DNA synthesis inhibition are considered to be responsible for the cardiotoxicity induced by these agents. Protein quality control (PQC) has 3 major components, including the endoplasmic reticulum (ER), the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system, and participates in protein folding and degradation to maintain protein homeostasis. We have demonstrated that PQC dysfunction is a new causal mechanism for the development of cardiac hypertrophy and failure. Increasing evidence shows that anti-cancer drugs, such as tyrosine kinase inhibitors, proteasome inhibitors, anthracyclines and autophagy inhibitors, cause PQC dysfunction. Here, we provide an overview of the potential role of PQC dysfunction in the development of cardiovascular complications induced by anti-cancer drugs.     

Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies

The utility of anthracycline antineoplastic agents in the clinic is compromised by the risk of cardiotoxicity. It has been calculated that approximately 10% of patients treated with doxorubicin or its derivatives will develop cardiac complications up to 10 years after the cessation of chemotherapy. Oxidative stress has been established as the primary cause of cardiotoxicity. However, interventions reducing oxidative stress have not been successful at reducing the incidence of cardiotoxicity in patients treated with doxorubicin. New insights into the cardiomyocyte response to oxidative stress demonstrate that underlying differences between in vitro and in vivo toxicities may modulate the response to superoxide radicals and related compounds. This has led to potentially new uses for pre-existing drugs and new avenues of exploration to find better pharmacotherapies and interventions for the prevention of cardiotoxicity. However, much work still must be done to validate the clinical utility of these new approaches and proposed mechanisms. In this review, the authors have reviewed the molecular mechanisms of the pathogenesis of acute and chronic doxorubicin-induced cardiotoxicity and propose potential pharmacological interventions and treatment options to prevent or reverse this specific type of heart failure.     

Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro

The clinical use of doxorubicin, a highly active anticancer drug, is limited by its severe cardiotoxic side effects. Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity of doxorubicin. Carvedilol is an adrenergic blocking agent with potent anti-oxidant activity. In this study we investigated whether carvedilol has protective effects against doxorubicin-induced free radical production and apoptosis in cultured cardiac muscle cells, and we compared the effects of carvedilol to atenolol, a beta-blocker with no anti-oxidant activity. Reactive oxygen species (ROS) generation in cultured cardiac muscle cells (H9c2 cells) was evaluated by flow cytometry using dichlorofluorescein (DCF) and hydroethidine (HE). Apoptosis was assessed by measuring annexin V-FITC/propidium iodide double staining, DNA laddering, levels of expression of the pro-apoptotic protein Bax-alpha and the anti-apoptotic protein Bcl-2, and caspase-3 activity. Pre-treatment with carvedilol significantly attenuated the doxorubicin-induced increases in DCF (P < 0.001 compared to cells not pre-treated with carvedilol) and HE (P < 0.01) fluorescence. Doxorubicin increased the fraction of annexin V-FITC-positive fluorescent cells, while pre-treatment with carvedilol reduced the number of positive fluorescent cells (P < 0.01). Doxorubicin-induced DNA fragmentation to a clear ladder pattern, while carvedilol prevented DNA fragmentation. Doxorubicin-induced a fall in mRNA expression of the anti-apoptotic Bcl-2 and an increase in the expression of the pro-apoptotic Bax-alpha. Carvedilol pre-treatment blunted both the decrease of Bcl-2 (P < 0.01) and the increase of Bax-alpha mRNA expression (P < 0.01). Caspase-3 activity significantly increased after the addition of doxorubicin. Concurrently, carvedilol partially inhibited the doxorubicin-induced activation of caspase-3 (P < 0.01). Atenolol did not produce any effect in preventing doxorubicin-induced ROS generation and cardiac apoptosis. Our results suggest that carvedilol is potentially protective against doxorubicin cardiotoxicity by decreasing free radical release and apoptosis in cardiomyocytes.     

Protection by flavonoids against anthracycline cardiotoxicity: from chemistry to clinical trials

Cardiotoxic side-effects of doxorubicin limit the clinical use of this anti-cancer agent. Iron chelators have been studied as protectors against doxorubicin-induced cardiotoxicity. These iron chelators do not provide optimal protection and have certain drawbacks. We therefore looked for new protectors and decided that these new compounds should combine iron chelating and antioxidant activity. Flavonoids appeared to possess those combined iron chelating and antioxidant properties. Quantum chemical evaluation of radical stabilization and determination of physico-chemical properties of a series of flavonoids brought our attention to the semi-synthetic flavonoid 7-monohydroxyetylrutoside (monoHER). Both in vitro (using an electrically paced mouse left atrium model) and in vivo (using a mouse ECG telemetry model) experiments corroborated the protective effect of monoHER. MonoHER also showed anti-inflammatory properties. A subsequent clinical phase I study showed that an i.v. dose of 1,500 mg/m² is a feasible and safe dose to be evaluated in a phase II study to investigate the protective properties of monoHER against doxorubicin-induced cardiotoxicity in cancer patients.     

Elevated myocardial Akt signaling ameliorates doxorubicin-induced congestive heart failure and promotes heart growth

Doxorubicin is a chemotherapeutic agent that can induce cardiotoxicity and congestive heart failure (CHF). In this study we tested whether intracoronary Akt1 gene delivery could inhibit doxorubicin-induced CHF. Saline or a replication defective adenoviral vector expressing constitutively-active Akt1 (myrAkt) or beta-galactosidase (betagal) was delivered to the myocardium of 8 week old rats one day prior to initiating doxorubicin administration. In animals receiving saline or betagal, doxorubicin resulted in significant decreases in cardiac function and retarded post-natal heart growth at the 5 weeks time point. In contrast, transduction of myrAkt protected hearts against doxorubicin-induced decreases in fractional shortening and cardiac index, and improved left ventricular function at 5 weeks time point. Delivery of myrAkt also reversed the doxorubicin-induced reduction in post-natal heart growth and diminished lung edema. These data show that myocardial Akt can inhibit doxorubicin-induced reductions in cardiac function and growth, suggesting that manipulation of this signaling pathway may have utility for the treatment of congestive heart failure.     

Proteomic insights into chronic anthracycline cardiotoxicity

Chronic anthracycline cardiotoxicity is a feared complication of cancer chemotherapy. However, despite several decades of primarily hypothesis-driven research, the molecular basis of this phenomenon remains poorly understood. The aim of this study was to obtain integrative molecular insights into chronic anthracycline cardiotoxicity and the resulting heart failure. Cardiotoxicity was induced in rabbits (daunorubicin 3 mg/kg, weekly, 10 weeks) and changes in the left ventricular proteome were analyzed by 2D-DIGE. The protein spots with significant changes (p < 0.01, > 1.5-fold) were identified using MALDI-TOF/TOF. Key data were corroborated by immunohistochemistry, qRT-PCR and enzyme activity determination and compared with functional, morphological and biochemical data. The most important alterations were found in mitochondria — especially in proteins crucial for oxidative phosphorylation, energy channeling, antioxidant defense and mitochondrial stress. Furthermore, the intermediate filament desmin, which interacts with mitochondria, was determined to be distinctly up-regulated and disorganized in its expression pattern. Interestingly, the latter changes reflected the intensity of toxic damage in whole hearts as well as in individual cells. In addition, a marked drop in myosin light chain isoforms, activation of proteolytic machinery (including the proteasome system), increased abundance of chaperones and proteins involved in chaperone-mediated autophagy, membrane repair as well as apoptosis were found. In addition, dramatic changes in proteins of basement membrane and extracellular matrix were documented. In conclusion, for the first time, the complex proteomic signature of chronic anthracycline cardiotoxicity was revealed which enhances our understanding of the basis for this phenomenon and it may enhance efforts in targeting its reduction.     

Doxorubicin-induced second degree and complete atrioventricular block.

Doxorubicin is one of the most effective chemotherapeutic agents used in the treatment of malignancies. Cardiotoxicity is the most important dose-limiting toxicity of doxorubicin. Although cardiomyopathy is the most well known side effect of doxorubicin, it usually occurs many years after the treatment and relates to cumulative doxorubicin dosage. Another form of doxorubicin cardiotoxicity is arrhythmia which may occur at any time and after any dosage. However, doxorubicin-induced arrhythmia is rarely a life-threatening side effect. In this report, we present a case in which there were doxorubicin-induced life-threatening arrhythmias.     

Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice

Doxorubicin is an effective chemotherapeutic drug against a considerable number of malignancies. However, its toxic effects on myocardium are confirmed as major limit of utilization. PPAR-α is highly expressed in the heart, and its activation leads to an increased cardiac fatty acid oxidation and cardiomyocyte necrosis. This study was performed to adjust the hypothesis that PPAR-α receptor inhibition protects against doxorubicin-induced cardiac dysfunction in mice. Male Balb/c mice were used in this study. Left atria were isolated, and their contractility was measured in response to electrical field stimulation in a standard organ bath. PPAR-α activity was measured using specific PPAR-α antibody in an ELISA-based system coated with double-strand DNA containing PPAR-α response element sequence. Moreover, cardiac MDA and TNF-α levels were measured by ELISA method. Following incubation with doxorubicin (35 µM), a significant reduction in atrial contractility was observed (P < 0.001). Pretreatment of animals with a selective PPAR-α antagonist, GW6471, significantly improved doxorubicin-induced atrial dysfunction (P < 0.001). Furthermore, pretreatment of the mice with a non-selective cannabinoid agonist, WIN55212-2, significantly decreased PPAR-α activity in cardiac tissue, subsequently leading to significant improvement in doxorubicin-induced atrial dysfunction (P < 0.001). Also, GW6471 and WIN significantly reduced cardiac MDA and TNF-α levels compared with animals receiving doxorubicin (P < 0.001). The study showed that inhibition of PPAR-α is associated with protection against doxorubicin-induced cardiotoxicity in mice, and cannabinoids can potentiate the protection by PPAR-α blockade. Moreover, PPAR-α may be considered as a target to prevent cardiotoxicity induced by doxorubicin in patients undergoing chemotherapy.     

Doxorubicin-induced cardiomyopathy 17 years after chemotherapy

Doxorubicin, an anthracycline antibiotic commonly used as a chemotherapeutic agent for breast cancer, is well known to cause cardiotoxicity. We report the case of an active, otherwise healthy 57-year-old breast cancer survivor who, 17 years after chemotherapy, presented with symptoms of overt heart failure. She had no cardiac risk factors, and neither laboratory nor imaging findings suggested myocarditis or dilated cardiomyopathy. Echocardiographic findings and differential diagnosis led us to attribute her condition to late doxorubicin-induced cardiomyopathy. By virtue of tapered medical therapy, her left ventricular ejection fraction improved from 0.20 to 0.55 in 8 months, and she was asymptomatic after 1 year. The reversibility of left ventricular dysfunction in our patient and the very late appearance of cardiotoxicity secondary to doxorubicin therapy raise questions about the pathogenesis and prevalence of late doxorubicin-induced cardiomyopathy and how to improve outcomes in patients who present with related symptoms of heart failure.     

Dystrophin-deficiency increases the susceptibility to doxorubicin-induced cardiotoxicity

BACKGROUND AND AIM: The clinical use of doxorubicin (DOX) and other anthracyclines is limited by a dosage-dependent cardiotoxicity, which can lead to cardiomyopathy. The role of the individual genetic makeup in this disorder is poorly understood. Alterations in genes encoding cardiac cytoskeleton or sarcolemma proteins may increase the susceptibility to doxorubicin-related cardiotoxicity. METHODS: Female dystrophin-deficient mice (MDX) and age-matched wild-type mice underwent chronic treatment with doxorubicin. Cardiac function and tissue damage were assessed by echocardiography and histopathology, respectively. Gene expression changes were investigated using microarrays. RESULTS: DOX treatment resulted in mortality, cardiac insufficiency, and cardiac interstitial fibrosis. These alterations were more pronounced in DOX-treated MDX mice than in DOX-treated wild-type mice. Changes in gene expression were more numerous in MDX mice, including genes involved in cell adhesion, oxidative stress, cytoskeleton organization, inflammatory and immune response and cell death. CONCLUSIONS: Dystrophin deficiency facilitates the development and progression of doxorubicin-induced cardiac injury. The underlying mechanisms may involve changes in cell adhesion, in cytoskeleton, as well as in inflammatory and immune responses. Genetic variants of cytoskeletal proteins in humans may affect the individual susceptibility to doxorubicin. Cardiotoxic drugs may accelerate the manifestation of pre-clinical cardiomyopathies caused by deficiencies in cytoskeletal or sarcolemma proteins.