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Thanks to the fantastic progress in cancer therapy options, there is a growing population of cancer survivors. This success has resulted in a need to focus much effort into improving the quality of life of this population. Cancer and cardiovascular disease share many common risk factors and have an interplay between them, with one condition mechanistically affecting the other and vice versa. Furthermore, widely prescribed cancer therapies have known toxic effects in the cardiovascular system. Anthracyclines are the paradigm of efficacious cancer therapy widely prescribed with a strong cardiotoxic potential. While some cancer therapies cardiovascular toxicities are transient, others are irreversible. There is a growing need to develop cardioprotective therapies that, when used in conjunction with cancer therapies, can prevent cardiovascular toxicity and thus improve long-term quality of life in survivors. The field has three main challenges: (i) identification of the ultimate mechanisms leading to cardiotoxicity to (ii) identify specific therapeutic targets, and (iii) more sensible diagnostic tools to early identify these conditions. In this review we will focus on the cardioprotective strategies tested and under investigation. We will focus this article into anthracycline cardiotoxicity since it is still the agent most widely prescribed, the one with higher toxic effects on the heart, and the most widely studied.
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ß3-Adrenergic receptor (ß3AR) agonists have been shown to protect against ischemia-reperfusion injury (IRI). Since ß3ARs are present both in cardiomyocytes and in endothelial cells, the cellular compartment responsible for this protection has remained unknown. Using transgenic mice constitutively expressing the human ß3AR (hß3AR) in cardiomyocytes or in the endothelium on a genetic background of null endogenous ß3AR expression, we show that only cardiomyocyte expression protects against IRI (45 min ischemia followed by reperfusion over 24 h). Infarct size was also limited after ischemia-reperfusion in mice with cardiomyocyte hß3AR overexpression on top of endogenous ß3AR expression. hß3AR overexpression in these mice reduced IRI-induced cardiac fibrosis and improved long-term left ventricular systolic function. Cardiomyocyte-specific ß3AR overexpression resulted in a baseline remodeling of the mitochondrial network, characterized by upregulated mitochondrial biogenesis and a downregulation of mitochondrial quality control (mitophagy), resulting in elevated numbers of small mitochondria with a depressed capacity for the generation of reactive oxygen species but improved capacity for ATP generation. These processes precondition cardiomyocyte mitochondria to be more resistant to IRI. Upon reperfusion, hearts with hß3AR overexpression display a restoration in the mitochondrial quality control and a rapid activation of antioxidant responses. Strong protection against IRI was also observed in mice infected with an adeno-associated virus (AAV) encoding hß3AR under a cardiomyocyte-specific promoter. These results confirm the translational potential of increased cardiomyocyte ß3AR expression, achieved either naturally through exercise or artificially through gene therapy approaches, to precondition the cardiomyocyte mitochondrial network to withstand future insults.
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The occurrence of regeneration of the organs involved in respiratory gas exchange amongst vertebrates is heterogeneous. In some species of amphibians and fishes, the gills regenerate completely following resection or amputation, whereas in mammals, only partial, facultative regeneration of lung tissue occurs following injury. Given the homology between gills and lungs, the capacity of gill regeneration in aquatic species is of major interest in determining the underlying molecular or signalling pathways involved in respiratory organ regeneration. In the present study, we used adult zebrafish (Danio rerio) to characterize signalling pathways involved in the early stages of gill regeneration. Regeneration of the gills was induced by resection of gill filaments and observed over a period of up to 10â days. We screened for the effects on regeneration of the drugs SU5402, dorsomorphin and LY411575, which inhibit FGF, BMP or Notch signalling pathways, respectively. Exposure to each drug for 5â days significantly reduced regrowth of filament tips in regenerating tissue, compared with unresected controls. In separate experiments under normal conditions of regeneration, we used reverse transcription quantitative PCR and observed an increased expression of genes encoding for the bone morphogenetic factor, Bmp2b, fibroblast growth factor, Fgf8a, a transcriptional regulator (Her6) involved in Notch signalling, and Sonic Hedgehog (Shha), in regenerating gills at 10â day post-resection, compared with unresected controls. In situ hybridization confirmed that all four genes were expressed in regenerating gill tissue. This study implicates BMP, FGF, Notch and Shh signalling in gill regeneration in zebrafish.
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Branquias , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/metabolismo , Branquias/metabolismo , Proteínas Hedgehog , Transducción de Señal/genética , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Proteínas de Pez Cebra/genética , Mamíferos/metabolismoRESUMEN
The ability to continuously grow and regenerate the gills throughout life is a remarkable property of fish and amphibians. Considering that gill regeneration was first described over one century ago, it is surprising that the underlying mechanisms of cell and tissue replacement in the gills remain poorly understood. By contrast, the mammalian lung is a largely quiescent organ in adults but is capable of facultative regeneration following injury. In the course of the past decade, it has been recognized that lungs contain a population of stem or progenitor cells with an extensive ability to restore tissue; however, despite recent advances in regenerative biology of the lung, the signaling pathways that underlie regeneration are poorly understood. In this Review, we discuss the common evolutionary and embryological origins shared by gills and mammalian lungs. These are evident in homologies in tissue structure, cell populations, cellular function and genetic pathways. An integration of the literature on gill and lung regeneration in vertebrates is presented using a comparative approach in order to outline the challenges that remain in these areas, and to highlight the importance of using aquatic vertebrates as model organisms. The study of gill regeneration in fish and amphibians, which have a high regenerative potential and for which genetic tools are widely available, represents a unique opportunity to uncover common signaling mechanisms that may be important for regeneration of respiratory organs in all vertebrates. This may lead to new advances in tissue repair following lung disease.
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Branquias , Pulmón , Animales , Peces , Transducción de Señal , VertebradosRESUMEN
European sea bass (Dicentrarchus labrax) inhabits coastal waters and may be exposed to hypoxia at different life stages, requiring physiological and behavioral adaptation. In the present study, we attempted to determine whether regulation of hemoglobin (Hb) gene expression plays a role in the physiological response to chronic moderate hypoxia in whole larvae and hematopoietic tissues (head kidney and spleen) of juveniles. We also tested the hypothesis that hypoxia exposure at the larval stage could induce a long-term effect on the regulation of Hb gene expression. For this purpose, D. labrax were exposed to a non-lethal hypoxic condition (40% air saturation) at the larval stage from 28 to 50â days post-hatching (dph) and/or at the juvenile stage from 196 to 296â dph. Data obtained from larvae indicate that hypoxia induced a subtype-specific regulation of Hb gene expression, with a significant decrease of MN-Hbα3, MN-Hbß4 and MN-Hbß5 and increase of MN-Hbα2, LA-Hbα1 and LA-Hbß1 transcript levels. Hypoxia did not induce regulation of Hb gene expression in juveniles, except in the head kidney for those that experienced hypoxia at the larval stage. The latter exhibited a significant hypoxia-induced stimulation of MN-Hbα2, LA-Hbα1 and LA-Hbß1 gene expression, associated with stimulation of the PHD-3 gene involved in the hypoxia-inducible factor oxygen-sensing pathway. We conclude that subtype- and stage-specific regulation of Hb gene expression plays a role in the physiological response of D. labrax to cope with hypoxia and that early exposure to low oxygen concentration has a long-term effect on this response.
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Lubina/fisiología , Proteínas de Peces/genética , Regulación de la Expresión Génica , Hemoglobinas/genética , Adaptación Fisiológica , Anaerobiosis , Animales , Lubina/genética , Proteínas de Peces/metabolismo , Hemoglobinas/metabolismoRESUMEN
In the present study, we assessed the responses of the vasotocinergic and isotocinergic systems to chronic stress induced by cortisol administration in the gilthead sea bream (Sparus aurata). Pituitary and plasma arginine vasotocin (AVT) and isotocin (IT) levels, as well as hypothalamic pro-vasotocin (pro-VT) and pro-isotocin (pro-IT) mRNA expression levels, were analysed. In addition, the mRNA levels of three receptors, AVTR type V1a2, AVTR type V2 and ITR, were analysed in several target organs associated with the following physiological processes: (i) integration and control (hypothalamus), (ii) metabolism and its control (liver and hypothalamus), (iii) osmoregulation (gills) and (iv) stress response (head kidney). Specimens were injected intraperitoneally with slow-release implants (5 µL g(-1) body mass) containing coconut oil alone (control group) or with cortisol (50 µg g(-1) body mass; cortisol group). Both AVT and IT synthesis and release were correlated with plasma cortisol values, suggesting a potential interaction between both hormonal systems and cortisol administration. Our results suggest that the activation of hepatic metabolism as well as the hypothalamic control of metabolic processes provide the energy necessary to overcome stress, which could be partly mediated by AVTRs and ITR. Upregulation of branchial AVT and IT receptor expression following cortisol treatment suggests an involvement of the vasotocinergic and isotocinergic systems in the regulation of ion channels/transporters during stressful situations. Finally, changes in AVT and IT receptor mRNA expression in the head kidney suggest these nonapeptides participate in feedback mechanisms that regulate the synthesis/release of cortisol. Our results indicate a relationship between cortisol and both the vasotocinergic and isotocinergic systems during simulated chronic stress in S. aurata.
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Receptores de Vasopresinas/metabolismo , Dorada/metabolismo , Estrés Fisiológico/fisiología , Animales , Secuencia de Bases , Branquias/fisiología , Riñón Cefálico/metabolismo , Hidrocortisona/metabolismo , Hipotálamo/fisiología , Hígado/metabolismo , Masculino , Osmorregulación/fisiología , Oxitocina/análogos & derivados , Oxitocina/metabolismo , Hipófisis/fisiología , ARN Mensajero/metabolismo , Receptores de Vasopresinas/genética , Dorada/genética , Vasotocina/metabolismoRESUMEN
Background: Anthracycline-induced cardiotoxicity (AIC) debilitates quality of life in cancer survivors. Serial characterizations are lacking of the molecular processes occurring with AIC. Objectives: The aim of this study was to characterize AIC progression in a mouse model from early (subclinical) to advanced heart failure stages, with an emphasis on cardiac metabolism and mitochondrial structure and function. Methods: CD1 mice received 5 weekly intraperitoneal doxorubicin injections (5 mg/kg) and were followed by serial echocardiography for 15 weeks. At 1, 9, and 15 weeks after the doxorubicin injections, mice underwent fluorodeoxyglucose positron emission tomography, and hearts were extracted for microscopy and molecular analysis. Results: Cardiac atrophy was evident at 1 week post-doxorubicin (left ventricular [LV] mass 117 ± 26 mg vs 97 ± 25 mg at baseline and 1 week, respectively; P < 0.001). Cardiac mass nadir was observed at week 3 post-doxorubicin (79 ± 16 mg; P = 0.002 vs baseline), remaining unchanged thereafter. Histology confirmed significantly reduced cardiomyocyte area (167 ± 19 µm2 in doxorubicin-treated mice vs 211 ± 26 µm2 in controls; P = 0.004). LV ejection fraction declined from week 6 post-doxorubicin (49% ± 9% vs 61% ± 9% at baseline; P < 0.001) until the end of follow-up at 15 weeks (43% ± 8%; P < 0.001 vs baseline). At 1 week post-doxorubicin, when LV ejection fraction remained normal, reduced cardiac metabolism was evident from down-regulated markers of fatty acid oxidation and glycolysis. Metabolic impairment continued to the end of follow-up in parallel with reduced mitochondrial adenosine triphosphate production. A transient early up-regulation of nutrient-sensing and mitophagy markers were observed, which was associated with mitochondrial enlargement. Later stages, when mitophagy was exhausted, were characterized by overt mitochondrial fragmentation. Conclusions: Cardiac atrophy, global hypometabolism, early transient-enhanced mitophagy, biogenesis, and nutrient sensing constitute candidate targets for AIC prevention.
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Zebrafish (Danio rerio) are widely used animal models. Nevertheless, the mechanisms underlying hypoxia tolerance in this species have remained poorly understood. In the present study, we have determined the effects of hypoxia on blood-O2 transport properties and mitochondrial respiration rate in permeabilized muscle fibres of adult zebrafish exposed to either 1) a gradual decrease in O2 levels until fish lost equilibrium (~1â¯h, acute hypoxia), or 2) severe hypoxia (PO2â¯â¼â¯15â¯Torr) for 48â¯h (prolonged hypoxia). Acute, short-term hypoxia caused an increase in hemoglobin (Hb) O2 affinity (decrease in P50), due to a decrease in erythrocyte ATP after erythrocyte swelling. No changes in isoHb expression patterns were observed between hypoxic and normoxic treatments. Prolonged hypoxia elicited additional reponses on O2 consumption: lactate accumulated in the blood, indicating that zebrafish relied on glycolysis for ATP production, and mitochondrial respiration of skeletal muscle was overall significantly inhibited. In addition, male zebrafish had higher hypoxia tolerance (measured as time to loss of equilibrium) than females. The present study contributes to our understanding of the adaptive mechanisms that allow zebrafish, and by inference other fish species, to cope with low O2 levels.
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Hipoxia/sangre , Músculo Esquelético/metabolismo , Consumo de Oxígeno , Oxígeno/sangre , Pez Cebra/sangre , Animales , Transporte Biológico Activo , Hemoglobinas/metabolismo , Proteínas de Pez Cebra/metabolismoRESUMEN
In teleosts, a complex interaction between several endocrine axes modulates physiological functions related to metabolism, stress, and osmoregulation. Although many studies in fish underline the interconnection between the hypothalamic-pituitary-interrenal (HPI) and hypothalamic-pituitary-thyroid (HPT) endocrine axes, their relationship with the vasotocinergic and isotocinergic systems remains unknown. The aim of the present study is therefore to shed light on the potential cross-regulations between HPT, HPI, and the vasotocinergic and isotocinergic axes in gilthead sea bream (Sparus aurata) at hypothalamic, hypophyseal, and plasma levels. Sea breams were administered with intraperitoneal slow-release implants containing different doses of vasotocin (the active peptide in vasotocinergic system) or cortisol (the last component of HPI axis). Plasma osmolality was higher in active neuropeptides vasotocin (Avt)-treated fish, indicating an osmoregulatory function of this hormone. Low concentrations of Avt increased hypothalamic arginine vasotocin precursor (avt) mRNA levels and increased Avt storage in the pituitary. Avt treatment down-regulated hypothalamic arginine vasotocin receptor v1a-type (avtrv1a), suggesting a negative paracrine co-regulation of the HPI axis due to the close location of avtrv1a and adrenocorticotropin hormone (Acth) cells in the anterior pituitary. Furthermore, the up-regulation observed in arginine vasotocin receptor v2-type (avtrv2) suggests their involvement in metabolic and cortisol-related pathways in the hypothalamus. The decrease in isotocin (It) pituitary storage and the up-regulation of it receptor, observed in the Avt-treated group, reinforce the idea of an interconnection between the vasotocinergic and isotocinergic systems. Cortisol and Avt administration each inhibited the HPI axis, down-regulating crh gene expression in the absence of variations in corticotropin releasing hormone binding protein (crhbp). Finally, both hormonal treatments activated the HPT axis via up-regulation of trh and down-regulation of thrb. Our results provide evidence for strong interactions among the Avt/It, HPI, and HPT axes of marine teleosts, particularly at the hypothalamic level.
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Several physiological functions in fish are shaped by environmental stimuli received during early life. In particular, early-life hypoxia has been reported to have long-lasting effects on fish metabolism, with potential consequences for fish life history traits. In the present study, we examine whether the synergistic stressors hypoxia (40% and 100% air saturation) and temperature (15° and 20°C), encountered during early life, could condition later metabolic response in European sea bass (Dicentrarchus labrax) juveniles. Growth rate and metabolic parameters related to carbohydrate and lipid metabolism in the liver were investigated at the juvenile stage under normoxic and chronic hypoxic conditions. Juvenile growth rates were significantly lower (p<1×10-6) under hypoxic conditions and were not improved by prior early-life exposure to hypoxia. Growth was 1.3 times higher (p<5×10-3) in juveniles reared at 15°C during the larval stage than those reared at 20°C, suggesting that compensatory growth had occurred. Early-life exposure to hypoxia induced higher (p<2×10-6) glycogen stores in juveniles even though there was no apparent regulation of their carbohydrate metabolism. In the liver of juveniles exposed to chronic hypoxia, lower glycogen content combined with stimulation of phosphoenolpyruvate carboxykinase gene expression and higher lactate concentration indicated a stimulation of the anaerobic glycolytic pathway. Furthermore, hypoxia only induced lower (p<1×10-3) lipid content in the liver of juveniles that had experienced 15°C at the larval stage. The present study provides evidence that environmental conditions experienced during early life shape the metabolic traits of D. labrax with potential consequences for juvenile physiological performance.
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Adaptación Fisiológica , Lubina/metabolismo , Metabolismo de los Hidratos de Carbono , Hipoxia/metabolismo , Metabolismo de los Lípidos , Animales , Europa (Continente)RESUMEN
Environmental conditions, to which organisms are exposed during all their life, may cause possible adaptive responses with consequences in their subsequent life-history trajectory. The objective of this study was to investigate whether ecologically relevant combinations of hypoxia (40% and 100% air saturation) and temperature (15° and 20⯰C), occurring during the larval period of European sea bass larvae (Dicentrarchus labrax), could have long-lasting impacts on the physiology of resulting juveniles. Hypoxic challenge tests were performed over one year to give an integrative evaluation of physiological performance. We revealed that juvenile performance was negatively impacted by hypoxia but not by the thermal conditions experienced at larval stage. This impact was related to the prevalence of opercular abnormalities. The present study indicates that exposure to a moderate hypoxia event during larval stage may have adverse carry-over effects, which could compromise fitness and population recruitment success.