RESUMEN
The use of doxorubicin (DOXO) as a chemotherapeutic drug has been hampered by cardiotoxicity leading to cardiomyopathy and heart failure. Folic acid (FA) is a modulator of endothelial nitric oxide (NO) synthase (eNOS), which in turn is an important player in diseases associated with NO insufficiency or NOS dysregulation, such as pressure overload and myocardial infarction. However, the role of FA in DOXO-induced cardiomyopathy is poorly understood. The aim of this study was to test the hypothesis that FA prevents DOXO-induced cardiomyopathy by modulating eNOS and mitochondrial structure and function. Male C57BL/6 mice were randomized to a single dose of DOXO (20 mg/kg intraperitoneal) or sham. FA supplementation (10 mg/day per oral) was started 7 days before DOXO injection and continued thereafter. DOXO resulted in 70% mortality after 10 days, with the surviving mice demonstrating a 30% reduction in stroke volume compared with sham groups. Pre-treatment with FA reduced mortality to 45% and improved stroke volume (both P < 0.05 versus DOXO). These effects of FA were underlain by blunting of DOXO-induced cardiomyocyte atrophy, apoptosis, interstitial fibrosis and impairment of mitochondrial function. Mechanistically, pre-treatment with FA prevented DOXO-induced increases in superoxide anion production by reducing the eNOS monomer:dimer ratio and eNOS S-glutathionylation, and attenuated DOXO-induced decreases in superoxide dismutase, eNOS phosphorylation and NO production. Enhancing eNOS function by restoring its coupling and subsequently reducing oxidative stress with FA may be a novel therapeutic approach to attenuate DOXO-induced cardiomyopathy.
Asunto(s)
Antioxidantes/farmacología , Cardiomiopatías/prevención & control , Cardiotónicos/farmacología , Cardiotoxicidad/prevención & control , Doxorrubicina/antagonistas & inhibidores , Doxorrubicina/toxicidad , Ácido Fólico/farmacología , Animales , Antibióticos Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Cardiomiopatías/inducido químicamente , Cardiomiopatías/enzimología , Cardiomiopatías/mortalidad , Cardiotoxicidad/enzimología , Cardiotoxicidad/mortalidad , Cardiotoxicidad/patología , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Mitocondrias/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Volumen Sistólico/efectos de los fármacos , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxidos/antagonistas & inhibidores , Superóxidos/metabolismo , Análisis de SupervivenciaRESUMEN
Nitric oxide (NO) produced by endothelial NO synthase (eNOS) exerts beneficial effects in a variety of cardiovascular disease states. Studies on the benefit of eNOS activity in pressure-overload cardiac hypertrophy and dysfunction produced by aortic stenosis are equivocal, which may be due to different expression levels of eNOS or different severities of pressure-overload. Consequently, we investigated the effects of eNOS-expression level on cardiac hypertrophy and dysfunction produced by mild or severe pressure-overload. To unravel the impact of eNOS on pressure-overload cardiac dysfunction we subjected eNOS deficient, wildtype and eNOS overexpressing transgenic (eNOS-Tg) mice to 8weeks of mild or severe transverse aortic constriction (TAC) and studied cardiac geometry and function at the whole organ and tissue level. In both mild and severe TAC, lack of eNOS ameliorated, whereas eNOS overexpression aggravated, TAC-induced cardiac remodeling and dysfunction. Moreover, the detrimental effects of eNOS in severe TAC were associated with aggravation of TAC-induced NOS-dependent oxidative stress and by further elevation of eNOS monomer levels, consistent with enhanced eNOS uncoupling. In the presence of TAC, scavenging of reactive oxygen species with N-acetylcysteine reduced eNOS S-glutathionylation, eNOS monomer and NOS-dependent superoxide levels in eNOS-Tg mice to wildtype levels. Accordingly, N-acetylcysteine improved cardiac function in eNOS-Tg but not in wildtype mice with TAC. In conclusion, independent of the severity of TAC, eNOS aggravates cardiac remodeling and dysfunction, which appears due to TAC-induced eNOS uncoupling and superoxide production.
Asunto(s)
Cardiomegalia/enzimología , Cardiomegalia/genética , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico/metabolismo , Remodelación Ventricular , Acetilcisteína/farmacología , Animales , Aorta/cirugía , Cardiomegalia/etiología , Cardiomegalia/patología , Constricción Patológica/complicaciones , Constricción Patológica/cirugía , Activación Enzimática , Femenino , Depuradores de Radicales Libres/farmacología , Eliminación de Gen , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo , Índice de Severidad de la Enfermedad , Superóxidos/antagonistas & inhibidores , Superóxidos/metabolismoRESUMEN
Oxidative stress greatly influences the pathogenesis of various cardiovascular disorders. Coronary interventions, including balloon angioplasty and coronary stent implantation, are associated with increased vascular levels of reactive oxygen species in conjunction with altered endothelial cell and smooth muscle cell function. These alterations potentially lead to restenosis, thrombosis, or endothelial dysfunction in the treated artery. Therefore, the understanding of the pathophysiological role of reactive oxygen species (ROS) generated during or after coronary interventions, or both, is essential to improve the success rate of these procedures. Superoxide O2(·-) anions, whether derived from uncoupled endothelial nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, xanthine oxidase, or mitochondria, are among the most harmful ROS. O2(·-) can scavenge nitric oxide, modify proteins and nucleotides, and induce proinflammatory signaling, which may lead to greater ROS production. Current innovations in stent technologies, including biodegradable stents, nitric oxide donor-coated stents, and a new generation of drug-eluting stents, therefore address persistent oxidative stress and reduced nitric oxide bioavailability after percutaneous coronary interventions. This review discusses the molecular mechanisms of ROS generation after coronary interventions, the related pathological events-including restenosis, endothelial dysfunction, and stent thrombosis-and possible therapeutic ways forward.
Asunto(s)
Reestenosis Coronaria/patología , Estrés Oxidativo/fisiología , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/métodos , Especies Reactivas de Oxígeno/metabolismo , Stents , Adulto , Anciano , Angioplastia Coronaria con Balón/efectos adversos , Angioplastia Coronaria con Balón/métodos , Reestenosis Coronaria/terapia , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/mortalidad , Estenosis Coronaria/terapia , Stents Liberadores de Fármacos , Endotelio Vascular/enzimología , Endotelio Vascular/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico , Óxido Nítrico Sintasa de Tipo III/metabolismo , Cuidados Posoperatorios/métodos , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/metabolismo , Complicaciones Posoperatorias/patología , Pronóstico , Radiografía , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Vasodilatadores/uso terapéuticoRESUMEN
Reactive oxygen species (ROS) are generated by several different cellular sources, and their accumulation within the myocardium is widely considered to cause harmful oxidative stress. On the other hand, their role as second messengers has gradually emerged. The equilibrium of the nitroso/redox balance between reactive nitrogen species and ROS is crucial for the health of cardiomyocytes. This review provides a comprehensive overview of sources of oxidative stress in cardiac myocytes and describes the role of the nitroso/redox balance in cardiac pathophysiology. Although the exact mechanism of ROS production by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox's) is not completely understood, Nox2 and Nox4 have particularly important roles within the myocardium. Increasing evidence suggests that Nox2 produces superoxide and Nox4 generates only hydrogen peroxide. We also discuss the key role of nitric oxide synthases (NOSs) in the maintenance of the nitroso/redox balance: uncoupled endothelial NOS has been suggested to shift from nitric oxide to ROS production, contributing to increased oxidative stress within the myocardium. Furthermore, we highlight the importance of sequentially targeting and/or regulating the specific sources of oxidative and nitrosative stress to prevent and/or reverse myocardial dysfunction. Inhibition of NADPH oxidase-dependent ROS is considered to be a potential strategy for treatment of cardiomyopathy. Neither in vivo nor clinical data are available for NADPH oxidase inhibitors. Specifically targeting the mitochondria with the antioxidant MitoQ would be a very promising translation approach, because it could prevent mitochondrial permeability transition pore opening when ROS are produced during heart reperfusion. Enhancing NO signaling could also be a promising therapeutic approach against myocardial dysfunction.
Asunto(s)
Miocardio/patología , Estrés Oxidativo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Humanos , Oxidación-ReducciónRESUMEN
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.
Asunto(s)
Antibióticos Antineoplásicos/efectos adversos , Cardiomiopatías/inducido químicamente , Doxorrubicina/efectos adversos , Animales , Cardiomiopatías/diagnóstico , Cardiomiopatías/metabolismo , Cardiomiopatías/terapia , HumanosRESUMEN
Reactive oxygen species (ROS) are essential in vascular homeostasis but may contribute to vascular dysfunction when excessively produced. Superoxide anion (O(2)(·-)) can directly affect vascular tone by reacting with K(+) channels and indirectly by reacting with nitric oxide (NO), thereby scavenging NO and causing nitroso-redox imbalance. After myocardial infarction (MI), oxidative stress increases, favoring the imbalance and resulting in coronary vasoconstriction. Consequently, we hypothesized that ROS scavenging results in coronary vasodilation, particularly after MI, and is enhanced after inhibition of NO production. Chronically instrumented swine were studied at rest and during exercise before and after scavenging of ROS with N-(2-mercaptoproprionyl)-glycine (MPG, 20 mg/kg iv) in the presence or absence of prior inhibition of endothelial NO synthase (eNOS) with N(ω)-nitro-L-arginine (L-NNA, 20 mg/kg iv). In normal swine, MPG resulted in coronary vasodilation as evidenced by an increased coronary venous O(2) tension, and trends toward increased coronary venous O(2) saturation and decreased myocardial O(2) extraction. These effects were not altered by prior inhibition of eNOS. In MI swine, MPG showed a significant vasodilator effect, which surprisingly was abolished by prior inhibition of eNOS. Moreover, eNOS dimer/monomer ratio was decreased after MI, reflecting eNOS uncoupling. In conclusion, ROS exert a small coronary vasoconstrictor influence in normal swine, which does not involve scavenging of NO. This vasoconstrictor influence of ROS is slightly enhanced after MI. Since inhibition of eNOS abolished rather than augmented the vasoconstrictor influence of ROS in swine with MI, while eNOS dimer/monomer ratio was decreased, our data imply that uncoupled eNOS may be a significant source of O(2)(·-) after MI.
Asunto(s)
Circulación Coronaria , Músculo Liso Vascular/metabolismo , Infarto del Miocardio/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo , Superóxidos/metabolismo , Vasoconstricción , Animales , Presión Sanguínea , Circulación Coronaria/efectos de los fármacos , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiopatología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Femenino , Depuradores de Radicales Libres/farmacología , Homeostasis , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiopatología , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Consumo de Oxígeno , Multimerización de Proteína , Porcinos , Factores de Tiempo , Vasoconstricción/efectos de los fármacos , Vasodilatación , Función Ventricular IzquierdaRESUMEN
Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in maintaining vascular pressure by producing nitric oxide (NO); hence, it has a crucial role in the regulation of endothelial function. The bioavailability of eNOS-derived NO is crucial for this function and might be affected at multiple levels. Uncoupling of eNOS, with subsequently less NO and more superoxide generation, is one of the major underlying causes of endothelial dysfunction found in atherosclerosis, diabetes, hypertension, cigarette smoking, hyperhomocysteinemia, and ischemia/reperfusion injury. Therefore, modulating eNOS uncoupling by stabilizing eNOS activity, enhancing its substrate, cofactors, and transcription, and reversing uncoupled eNOS are attractive therapeutic approaches to improve endothelial function. This review provides an extensive overview of the important role of eNOS uncoupling in the pathogenesis of endothelial dysfunction and the potential therapeutic interventions to modulate eNOS for tackling endothelial dysfunction.
Asunto(s)
Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico/metabolismo , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/metabolismo , Animales , Endotelio Vascular/fisiopatología , Inducción Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Estabilidad de Enzimas/efectos de los fármacos , Humanos , Óxido Nítrico/agonistas , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/química , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Células Madre/efectos de los fármacos , Células Madre/enzimología , Células Madre/metabolismo , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/fisiopatologíaRESUMEN
Heart failure (HF) occurs when the adaptation mechanisms of the heart fail to compensate for stress factors, such as pressure overload, myocardial infarction, inflammation, diabetes, and cardiotoxic drugs, with subsequent ventricular hypertrophy, fibrosis, myocardial dysfunction, and chamber dilatation. Oxidative stress, defined as an imbalance between reactive oxygen species (ROS) generation and the capacity of antioxidant defense systems, has been authenticated as a pivotal player in the cardiopathogenesis of the various HF subtypes. The family of NADPH oxidases has been investigated as a key enzymatic source of ROS in the pathogenesis of HF. In this review, we discuss the importance of NADPH oxidase-dependent ROS generation in the various subtypes of HF and its implications. A better understanding of the pathogenic roles of NADPH oxidases in the failing heart is likely to provide novel therapeutic strategies for the prevention and treatment of HF.
Asunto(s)
Insuficiencia Cardíaca/enzimología , NADPH Oxidasas/metabolismo , Estrés Oxidativo , Animales , Cardiomiopatías Diabéticas/enzimología , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/prevención & control , Doxorrubicina/efectos adversos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Humanos , Hipertensión/complicaciones , Miocarditis/complicaciones , NADPH Oxidasas/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Remodelación VentricularRESUMEN
RATIONALE: One of the physiological mechanisms by which the heart adapts to a rise in blood pressure is by augmenting myocyte stretch-mediated intracellular calcium, with a subsequent increase in contractility. This slow force response was first described over a century ago and has long been considered compensatory, but its underlying mechanisms and link to chronic adaptations remain uncertain. Because levels of the matricellular protein thrombospondin-4 (TSP4) rapidly rise in hypertension and are elevated in cardiac stress overload and heart failure, we hypothesized that TSP4 is involved in this adaptive mechanism. OBJECTIVE: To determine the mechano-transductive role that TSP4 plays in cardiac regulation to stress. METHODS AND RESULTS: In mice lacking TSP4 (Tsp4â»/â»), hearts failed to acutely augment contractility or activate stretch-response pathways (ERK1/2 and Akt) on exposure to acute pressure overload. Sustained pressure overload rapidly led to greater chamber dilation, reduced function, and increased heart mass. Unlike controls, Tsp4â»/â» cardiac trabeculae failed to enhance contractility and cellular calcium after a stretch. However, the contractility response was restored in Tsp4â»/â» muscle incubated with recombinant TSP4. Isolated Tsp4â»/â» myocytes responded normally to stretch, identifying a key role of matrix-myocyte interaction for TSP4 contractile modulation. CONCLUSION: These results identify TSP4 as myocyte-interstitial mechano-signaling molecule central to adaptive cardiac contractile responses to acute stress, which appears to play a crucial role in the transition to chronic cardiac dilatation and failure.
Asunto(s)
Contracción Miocárdica/fisiología , Miocitos Cardíacos/fisiología , Estrés Fisiológico/fisiología , Trombospondinas/fisiología , Animales , Insuficiencia Cardíaca/fisiopatología , Hipertensión/fisiopatología , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Miocitos Cardíacos/citología , Proteínas Proto-Oncogénicas c-akt/fisiología , Ratas , Trombospondinas/deficiencia , Trombospondinas/genéticaRESUMEN
The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-coupled endothelial NOS (eNOS), with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling. However, recent studies suggest the effective BH4 dosing may be narrower than previously thought, potentially due to its oxidation upon oral consumption. Accordingly, we assessed the dose response of daily oral synthetic sapropterin dihydrochloride (6-R-l-erythro-5,6,7,8-tetrahydrobiopterin, 6R-BH4) on pre-established pressure-overload cardiac disease. Mice (n=64) were administered 0-400mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200mg/kg/d, 6R-BH4 suppressed cardiac chamber remodeling, hypertrophy, fibrosis, and oxidative stress with pressure-overload. However, at both lower and higher doses, BH4 had less or no ameliorative effects. The effective doses correlated with a higher myocardial BH4/BH2 ratio. However, BH2 rose linearly with dose, and at the 400mg/kg/d, this lowered the BH4/BH2 ratio back toward control. These results expose a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''
Asunto(s)
Biopterinas/análogos & derivados , Cardiotónicos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Remodelación Ventricular/efectos de los fármacos , Análisis de Varianza , Animales , Biopterinas/metabolismo , Biopterinas/farmacocinética , Biopterinas/uso terapéutico , Cardiotónicos/farmacocinética , Relación Dosis-Respuesta a Droga , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Ligadura , Ratones , Ratones Endogámicos C57BL , Miocardio/patología , Distribución Aleatoria , Superóxidos/metabolismo , Función Ventricular IzquierdaRESUMEN
The pathogenesis of many cardiovascular diseases is associated with reduced nitric oxide (NO) bioavailability and/or increased endothelial NO synthase (eNOS)-dependent superoxide formation. These findings support that restoring and conserving adequate NO signaling in the heart and blood vessels is a promising therapeutic intervention. In particular, modulating eNOS, e.g., through increasing the bioavailability of its substrate and cofactors, enhancing its transcription, and interfering with other modulators of eNOS pathway, such as netrin-1, has a high potential for effective treatments of cardiovascular diseases. This review provides an overview of the possibilities for modulating eNOS and how this may be translated to the clinic in addition to describing the genetic models used to study eNOS modulation.
Asunto(s)
Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico/metabolismo , Animales , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/fisiopatología , Endotelio Vascular/enzimología , Endotelio Vascular/fisiopatología , Inhibidores Enzimáticos/uso terapéutico , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Donantes de Óxido Nítrico/uso terapéutico , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/genética , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Tetrahydrobiopterin (BH(4)) is an essential cofactor for aromatic amino acid hydroxylases and for all three nitric oxide synthase (NOS) isoforms. It also has a protective role in the cell as an antioxidant and scavenger of reactive nitrogen and oxygen species. Experimental studies in humans and animals demonstrate that decreased BH(4)-bioavailability, with subsequent uncoupling of endothelial NOS (eNOS) plays an important role in the pathogenesis of endothelial dysfunction, hypertension, ischemia-reperfusion injury, and pathologic cardiac remodeling. Synthetic BH(4) is clinically approved for the treatment of phenylketonuria, and experimental studies support its capacity for ameliorating cardiovascular pathophysiologies. To date, however, the translation of these studies to human patients remains limited, and early results have been mixed. In this review, we discuss the pathophysiologic role of decreased BH(4) bioavailability, molecular mechanisms regulating its metabolism, and its potential therapeutic use as well as pitfalls as an NOS-modulating drug. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''