RESUMEN

Mucopolysaccharidosis type II (MPSII) is a progressive lysosomal storage disease caused by mutations in the IDS gene, that leads to iduronate 2-sulfatase (IDS) enzyme deficiency. The enzyme catalyzes the first step of degradation of two glycosaminoglycans (GAGs), heparan sulfate (HS) and dermatan sulfate (DS). The consequences of MPSII are progressively harmful and can lead to death by cardiac failure. The aim of this study was to characterize the cardiovascular disease in MPSII mice. Thus, we evaluated the cardiovascular function of MPSII male mice at 6, 8, and 10 months of age, through functional, histological, and biochemical analyzes. Echocardiographic analyses showed a progressive loss in cardiac function, observed through parameters such as reduction in ejection fraction (46% in control versus 28% in MPS II at 10 months, P < .01) and fractional area change (31% versus 23%, P < .05). Similar results were found in parameters of vascular competence, obtained by echo Doppler. Both aortic dilatation and an increase in pulmonary resistance were observed at all time points in MPSII mice. The histological analyses showed an increase in the thickness of the heart valves (2-fold thicker than control values at 10 months). Biochemical analyzes confirmed GAG storage in these tissues, with a massive elevation of DS in the myocardium. Furthermore, an important increase in the activity of proteases such as cathepsin S and B (up to 5-fold control values) was found and could be related to the progressive loss of cardiac function observed in MPSII mice. In this work, we demonstrated that loss of cardiac function in MPSII mice started at 6 months of age, although its global cardiac capacity was still preserved at this time. Disease progressed at later time points leading to heart failure. The MPSII mice at later times reproduce many of the cardiovascular events found in patients with Hunter's disease.

RESUMEN

CONTEXT: Infarction leads to a decrease in NO bioavailability in the erythrocytes. Thyroid hormones (TH) present positive effects after infarction. However, there are no studies evaluating the effects of cardioprotective doses of TH in the erythrocytes after infarction. OBJECTIVE: This study aimed to evaluate the effects of TH in NO bioavailability and oxidative stress parameters in the erythrocytes of infarcted rats. MATERIAL AND METHODS: Wistar rats were allocated into the three groups: Sham-operated (SHAM), infarcted (AMI) and infarcted + TH (AMIT). AMIT rats received T4 and T3 for 12 days by gavage. Subsequently, the animals were evaluated by echocardiography and the LV and erythrocytes were collected. RESULTS: TH improved NO bioavailability and increased catalase activity in the erythrocytes. Besides that, TH increased HIF-1α in the heart. CONCLUSION: TH seems to be positive for erythrocytes preventing a decrease in NO bioavailability and increasing antioxidant enzymatic defense after infarction.

Asunto(s)

Antioxidantes , Infarto del Miocardio , Animales , Ratas , Catalasa , Eritrocitos , Infarto del Miocardio/prevención & control , Infarto del Miocardio/metabolismo , Ratas Wistar , Hormonas Tiroideas/farmacología , Óxido Nítrico

RESUMEN

Resumo Fundamento Até o presente momento, os efeitos sistêmicos do óleo de copaíba jamais foram documentados no Cor pulmonale induzido por monocrotalina. Objetivos Investigar os efeitos do óleo de copaíba nos marcadores periféricos de stress oxidativo em ratos com Cor pulmonale. Métodos Ratos Wistar machos (170±20g, n=7/grupo) foram divididos em quatro grupos: controle (CO), monocrotalina (MCT), óleo de copaíba (O), e monocrotalina + óleo de copaíba (MCT-O). Foi administrada a MCT (60 mg/kg i.p.) e, depois de uma semana, foi iniciado o tratamento com óleo de copaíba (400 mg/kg/day-gavagem-14 dias). Foi realizado o ecocardiograma e, depois disso, foi coletado sangue do tronco para a realização de avaliações de stress oxidativo. Análise estatística: ANOVA de duas vias com teste Student-Newman-Keuls post hoc. P-valores <0,05 foram considerados significativos. Resultados O óleo de copaíba reduziu a resistência vascular pulmonar e a hipertrofia do ventrículo direito (VD) hipertrofia (Índice de Fulton (mg/mg)): MCT-O= 0,39±0,03; MCT= 0,49±0,01), e função sistólica melhorada (fração de encurtamento do VD, %) no grupo MCT-O (17,8±8,2) em comparação com o grupo de MCT (9,4±3,1; p<0,05). Além disso, no grupo MCT-O, espécies reativas do oxigênio e os níveis de carbonila foram reduzidos, e os parâmetros antioxidantes aumentaram no sangue periférico (p <0,05). Conclusões Os resultados deste estudo sugerem que o óleo de copaíba tem um efeito antioxidante sistêmico interessante, que se reflete na melhoria da função e na morfometria do VD nesse modelo de Cor pulmonale . A atenuação do Cor pulmonale promovida pelo óleo de copaíba coincidiu com uma redução no stress oxidativo sistêmico.

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Abstract Background To date, copaiba oil's systemic effects have never documented in Cor pulmonale induced by monocrotaline. Objectives To investigate copaiba oil's effects in peripheral markers of oxidative stress in rats with Cor pulmonale. Methods Male Wistar rats (170±20g, n=7/group) were divided into four groups: control (CO), monocrotaline (MCT), copaiba oil (O), and monocrotaline+copaiba oil (MCT-O). MCT (60 mg/kg i.p.) was administered, and after one week, treatment with copaiba oil (400 mg/kg/day-gavage-14 days) was begun. Echocardiography was performed and, later, trunk blood collection was performed for oxidative stress evaluations. Statistical analysis: two-way ANOVA with Student-Newman-Keuls post-hoc test. P values<0.05 were considered significant. Results Copaiba oil reduced pulmonary vascular resistance and right ventricle (RV) hypertrophy (Fulton index (mg/mg): MCT-O=0.39±0.03; MCT=0.49±0.01), and improved RV systolic function (RV shortening fraction, %) in the MCT-O group (17.8±8.2) as compared to the MCT group (9.4±3.1; p<0.05). Moreover, in the MCT-O group, reactive oxygen species and carbonyl levels were reduced, and antioxidant parameters were increased in the peripheral blood (p<0.05). Conclusions: Our results suggest that copaiba oil has an interesting systemic antioxidant effect, which is reflected in the improvements in function and RV morphometry in this Cor pulmonale model. Cor pulmonale attenuation promoted by copaiba oil coincided with a reduction in systemic oxidative stress.

RESUMEN

BACKGROUND: To date, copaiba oil's systemic effects have never documented in Cor pulmonale induced by monocrotaline. OBJECTIVES: To investigate copaiba oil's effects in peripheral markers of oxidative stress in rats with Cor pulmonale. METHODS: Male Wistar rats (170±20g, n=7/group) were divided into four groups: control (CO), monocrotaline (MCT), copaiba oil (O), and monocrotaline+copaiba oil (MCT-O). MCT (60 mg/kg i.p.) was administered, and after one week, treatment with copaiba oil (400 mg/kg/day-gavage-14 days) was begun. Echocardiography was performed and, later, trunk blood collection was performed for oxidative stress evaluations. Statistical analysis: two-way ANOVA with Student-Newman-Keuls post-hoc test. P values<0.05 were considered significant. RESULTS: Copaiba oil reduced pulmonary vascular resistance and right ventricle (RV) hypertrophy (Fulton index (mg/mg): MCT-O=0.39±0.03; MCT=0.49±0.01), and improved RV systolic function (RV shortening fraction, %) in the MCT-O group (17.8±8.2) as compared to the MCT group (9.4±3.1; p<0.05). Moreover, in the MCT-O group, reactive oxygen species and carbonyl levels were reduced, and antioxidant parameters were increased in the peripheral blood (p<0.05). Conclusions: Our results suggest that copaiba oil has an interesting systemic antioxidant effect, which is reflected in the improvements in function and RV morphometry in this Cor pulmonale model. Cor pulmonale attenuation promoted by copaiba oil coincided with a reduction in systemic oxidative stress.

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FUNDAMENTO: Até o presente momento, os efeitos sistêmicos do óleo de copaíba jamais foram documentados no Cor pulmonale induzido por monocrotalina. OBJETIVOS: Investigar os efeitos do óleo de copaíba nos marcadores periféricos de stress oxidativo em ratos com Cor pulmonale. MÉTODOS: Ratos Wistar machos (170±20g, n=7/grupo) foram divididos em quatro grupos: controle (CO), monocrotalina (MCT), óleo de copaíba (O), e monocrotalina + óleo de copaíba (MCT-O). Foi administrada a MCT (60 mg/kg i.p.) e, depois de uma semana, foi iniciado o tratamento com óleo de copaíba (400 mg/kg/day-gavagem-14 dias). Foi realizado o ecocardiograma e, depois disso, foi coletado sangue do tronco para a realização de avaliações de stress oxidativo. Análise estatística: ANOVA de duas vias com teste Student-Newman-Keuls post hoc. P-valores <0,05 foram considerados significativos. RESULTADOS: O óleo de copaíba reduziu a resistência vascular pulmonar e a hipertrofia do ventrículo direito (VD) hipertrofia (Índice de Fulton (mg/mg)): MCT-O= 0,39±0,03; MCT= 0,49±0,01), e função sistólica melhorada (fração de encurtamento do VD, %) no grupo MCT-O (17,8±8,2) em comparação com o grupo de MCT (9,4±3,1; p<0,05). Além disso, no grupo MCT-O, espécies reativas do oxigênio e os níveis de carbonila foram reduzidos, e os parâmetros antioxidantes aumentaram no sangue periférico (p <0,05). CONCLUSÕES: Os resultados deste estudo sugerem que o óleo de copaíba tem um efeito antioxidante sistêmico interessante, que se reflete na melhoria da função e na morfometria do VD nesse modelo de Cor pulmonale . A atenuação do Cor pulmonale promovida pelo óleo de copaíba coincidiu com uma redução no stress oxidativo sistêmico.

Asunto(s)

Hipertensión Pulmonar , Enfermedad Cardiopulmonar , Animales , Masculino , Monocrotalina , Estrés Oxidativo , Enfermedad Cardiopulmonar/tratamiento farmacológico , Ratas , Ratas Wistar

RESUMEN

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by mutations in the IDUA gene, that codifies the alpha-L-iduronidase enzyme, which deficiency leads to storage of glycosaminoglycans, with multiple clinical manifestations. One of the leading causes of death in MPS I patients are cardiac complications such as cardiac valve thickening, conduction abnormalities, myocardial dysfunction, and cardiac hypertrophy. The mechanism leading to cardiac dysfunction in MPS I is not entirely understood. In a previous study, we have demonstrated that losartan and propranolol improved the cardiac function in MPS I mice. Thus, we aimed to investigate whether the pathways influenced by these drugs may modulate the cardiac remodeling process in MPS I mice. According to our previous observation, losartan and propranolol restore the heart function, without altering valve thickness. MPS I mice presented reduced activation of AKT and ERK1/2, increased activity of cathepsins, but no alteration in metalloproteinase activity was observed. Animals treated with losartan showed a reduction in cathepsin activity and restored ERK1/2 activation. While both losartan and propranolol improved heart function, no mechanistic evidence was found for propranolol so far. Our results suggest that losartan or propranolol could be used to ameliorate the cardiac disease in MPS I and could be considered as adjuvant treatment candidates for therapy optimization.

Asunto(s)

Cardiopatías/patología , Losartán/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mucopolisacaridosis I/tratamiento farmacológico , Remodelación Ventricular/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Ecocardiografía , Femenino , Cardiopatías/tratamiento farmacológico , Cardiopatías/genética , Iduronidasa/genética , Sistema de Señalización de MAP Quinasas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/patología , Mutación

RESUMEN

Mucopolysaccharidosis type I (MPS I) is caused by deficiency of alpha-L-iduronidase (IDUA), leading to multisystemic accumulation of glycosaminoglycans (GAG). Untreated MPS I patients may die in the first decades of life, mostly due to cardiovascular and respiratory complications. We previously reported that the treatment of newborn MPS I mice with intravenous administration of lipossomal CRISPR/Cas9 complexes carrying the murine Idua gene aiming at the ROSA26 locus resulted in long-lasting IDUA activity and GAG reduction in various tissues. Following this, the present study reports the effects of gene editing in cardiovascular, respiratory, bone, and neurologic functions in MPS I mice. Bone morphology, specifically the width of zygomatic and femoral bones, showed partial improvement. Although heart valves were still thickened, cardiac mass and aortic elastin breaks were reduced, with normalization of aortic diameter. Pulmonary resistance was normalized, suggesting improvement in respiratory function. In contrast, behavioral abnormalities and neuroinflammation still persisted, suggesting deterioration of the neurological functions. The set of results shows that gene editing performed in newborn animals improved some manifestations of the MPS I disorder in bone, respiratory, and cardiovascular systems. However, further studies will be imperative to find better delivery strategies to reach "hard-to-treat" tissues to ensure better systemic and neurological effects.

Asunto(s)

Iduronidasa/genética , Mucopolisacaridosis I/terapia , ARN no Traducido/genética , Animales , Animales Recién Nacidos , Enfermedades Óseas/genética , Sistemas CRISPR-Cas/genética , Sistema Cardiovascular/metabolismo , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Modelos Animales de Enfermedad , Femenino , Edición Génica/métodos , Terapia Genética/métodos , Glicosaminoglicanos/metabolismo , Iduronidasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/fisiopatología , Fenotipo , ARN no Traducido/metabolismo

RESUMEN

Unhealthy lifestyle persistently feeds forward inflammation in metabolic organs thus imposing senescence-associated secretory phenotype (SASP), as observed in obesity and type 2 diabetes. However, SASP blocks physiological resolution of inflammation by suppressing the anti-inflammatory and anti-senescent heat shock (HS) response, i.e., the gene program centered in heat shock factor-1 (HSF1)-dependent expression heat shock proteins (HSPs). As SASP-inducing factors are not removed, leading to the perpetuation of inflammation, we argued that SIRT1-HSF1-HSP axis might also be suppressed in atherosclerosis, which could be reversible by heat treatment (HT), the most powerful HS response trigger. LDLr-/- adult mice were fed on high-fat/high-cholesterol diet from the age of 90 days until the end of study (age of 270 days). After 120 days under atherosclerotic diet, the animals were submitted to either whole-body HT (n = 42; 40 °C) or sham (n = 59; 37 °C) treatment (15 min/session), under anesthesia, once a week, for 8 weeks, being echographically and metabolically monitored. Aortic expressions of SIRT1, HSF1, HSP27, HSP72 and HSP73 were progressively depressed in atherosclerotic animals, as compared to normal (LDLr+/+; n = 25) healthy counterparts, which was paralleled by increased expression of NF-κB-dependent VCAM1 adhesion molecule. Conversely, HT completely reversed suppression of the above HS response proteins, while markedly inhibiting both VCAM1 expression and NF-κB DNA-binding activity. Also, HT dramatically reduced plasma levels of TG, total cholesterol, LDL-cholesterol, oxidative stress, fasting glucose and insulin resistance while rising HDL-cholesterol levels. HT also decreased body weight gain, visceral fat, cellular infiltration and aortic fatty streaks, and heart ventricular congestive hypertrophy, thereby improving aortic blood flow and myocardial performance (Tei) indices. Remarkably, heat-treated mice stopped dying after the third HT session (= 8 human years), suggesting a curative effect. Therefore, evolution of atherosclerosis is associated with suppression of the anti-inflammatory and anti-senescent SIRT1-HSF1-HSP molecular axis, which is refreshed by chronic heat treatment.

Asunto(s)

Aorta/metabolismo , Aterosclerosis/terapia , Respuesta al Choque Térmico , Hipertermia Inducida , Animales , Aterosclerosis/inducido químicamente , Aterosclerosis/genética , Aterosclerosis/metabolismo , Colesterol/efectos adversos , Colesterol/farmacología , Grasas de la Dieta/efectos adversos , Grasas de la Dieta/farmacología , Regulación de la Expresión Génica , Proteínas de Choque Térmico/biosíntesis , Calor , Masculino , Ratones , Ratones Noqueados , Receptores de LDL/genética , Receptores de LDL/metabolismo , Sirtuina 1/biosíntesis

RESUMEN

There is an increase in oxidative stress and apoptosis signaling during the transition from hypertrophy to right ventricular (RV) failure caused by pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). In this study, it was evaluated the action of copaiba oil on the modulation of proteins involved in RV apoptosis signaling in rats with PAH. Male Wistar rats (±170 g, n = 7/group) were divided into 4 groups: control, MCT, copaiba oil, and MCT + copaiba oil. PAH was induced by MCT (60 mg/kg intraperitoneally) and, 7 days later, treatment with copaiba oil (400 mg/kg by gavage) was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and the RV was collected for morphometric evaluations, oxidative stress, apoptosis, and cell survival signaling, and eNOS protein expression. Copaiba oil reduced RV hypertrophy (24%), improved RV systolic function, and reduced RV end-diastolic pressure, increased total sulfhydryl levels and eNOS protein expression, reduced lipid and protein oxidation, and the expression of proteins involved in apoptosis signaling in the RV of MCT + copaiba oil as compared to MCT group. In conclusion, copaiba oil reduced oxidative stress, and apoptosis signaling in RV of rats with PAH, which may be associated with an improvement in cardiac function caused by this compound.

Asunto(s)

Apoptosis/efectos de los fármacos , Fármacos Cardiovasculares/farmacología , Fabaceae , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/prevención & control , Monocrotalina , Miocardio , Aceites de Plantas/farmacología , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Fármacos Cardiovasculares/aislamiento & purificación , Modelos Animales de Enfermedad , Fabaceae/química , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Aceites de Plantas/aislamiento & purificación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patología , Proteína X Asociada a bcl-2/metabolismo

RESUMEN

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder with multisystemic features, including heart enlargement, heart valve dysfunction, and aortic stiffness and dilatation. Previous studies have shown that MPS I mice overexpress cathepsin B (CtsB) in multiple tissues, including those from the cardiovascular system. Here, we hypothesized that inhibition of CtsB could ameliorate cardiac function parameters, as well as aorta and valve abnormalities found in MPS I. First, we found that total elastase activity in an MPS I aorta is elevated. Following that, we demonstrated that CtsB leaks from the lysosome in MPS I human fibroblasts, possibly acting as a degradative agent of extracellular matrix components from the aorta, cardiac muscle, and heart valves. We then used a CtsB inhibitor in vivo in the MPS I mouse model. After 4 months of treatment, partial inhibition of CtsB activity in treated mice reduced aortic dilatation, as well as heart valve thickening, and led to improvements in cardiac function parameters, although none of these were completely normalized. Based on these results, we conclude that lysosomal alterations in this disease promote leakage of CtsB to outside the organelle, where this protein can have multiple pathological roles. CtsB inhibition improved cardiovascular parameters in MPS I mice and can have a potential benefit in this disease.

Asunto(s)

Sistema Cardiovascular/patología , Catepsina B/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/uso terapéutico , Dipéptidos/uso terapéutico , Mucopolisacaridosis I/diagnóstico por imagen , Mucopolisacaridosis I/tratamiento farmacológico , Animales , Aorta/patología , Aorta/fisiopatología , Sistema Cardiovascular/diagnóstico por imagen , Catepsina B/metabolismo , Colagenasas/metabolismo , Femenino , Fibroblastos/metabolismo , Pruebas de Función Cardíaca , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Enfermedades de las Válvulas Cardíacas/tratamiento farmacológico , Enfermedades de las Válvulas Cardíacas/patología , Humanos , Lisosomas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mucopolisacaridosis I/patología , Elastasa Pancreática/metabolismo

RESUMEN

The aim of this study was to evaluate the impact of ovariectomy on oxidative stress in the right ventricle (RV) of female rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). Rats were divided into 4 groups (n = 6 per group): sham (S), sham + MCT (SM), ovariectomized (O), and ovariectomized + MCT (OM). MCT (60 mg·kg-1 i.p.) was injected 1 week after ovariectomy or sham surgery. Three weeks later, echocardiographic analysis and RV catheterisation were performed. RV morphometric, biochemical, and protein expression analysis through Western blotting were done. MCT promoted a slight increase in pulmonary artery pressure, without differences between the SM and OM groups, but did not induce RV hypertrophy. RV hydrogen peroxide increased in the MCT groups, but SOD, CAT, and GPx activities were also enhanced. Non-classical antioxidant defenses diminished in ovariectomized groups, probably due to a decrease in the nuclear factor Nrf2. Hemoxygenase-1 and thioredoxin-1 protein expression was increased in the OM group compared with SM, being accompanied by an elevation in the estrogen receptor ß (ER-ß). Hemoxygenase-1 and thioredoxin-1 may be involved in the modulation of oxidative stress in the OM group, and this could be responsible for attenuation of PAH and RV remodeling.

Asunto(s)

Antioxidantes/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Monocrotalina/efectos adversos , Ovariectomía/efectos adversos , Adaptación Fisiológica/efectos de los fármacos , Animales , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Hemodinámica/efectos de los fármacos , Hipertensión Pulmonar/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Remodelación Ventricular/efectos de los fármacos

Asunto(s)

Losartán , Mucopolisacaridosis I , Enfermedades de la Aorta , Enfermedades Cardiovasculares , Dilatación , Humanos

RESUMEN

Mucopolysaccharidosis type I (MPS I) is a lysosomal disorder characterized by a deficiency of alpha-L-iduronidase and storage of undegraded glycosaminoglycans (GAGs). Clinical findings of the disease include heart failure, and patients often need valve replacement. It has been shown that, later in life, MPS I mice develop those abnormalities, but to date, there have not been studies on the progression and pathogenesis of the disease. Therefore, in the present study, we evaluated heart function in normal and MPS I male mice from 2 to 8 months of age. Echocardiographic analysis showed left ventricular enlargement with progressive reduction in ejection fraction, fractional area change, and left ventricular fractional shortening in the MPS I hearts at 6 and 8 months of age and a reduction in acceleration time/ejection time ratio of the pulmonary artery starting at 6 months of age, which suggests pulmonary vascular resistance. Histological and biochemical analysis confirmed progressive GAG storage from 2 months of age and onwards in the myocardium and heart valves, which had also increased in thickness. Additionally, macrophages were present in the MPS I heart tissue. Collagen content was reduced in the MPS I mouse valves. Cathepsin B, an enzyme that is known to be able to degrade collagen and is involved in heart dilatation, displayed a marked elevation in activity in the MPS I mice and could be responsible for the heart dilatation and valves alterations observed. Our results suggest that the MPS I mice have progressive heart failure and valve disease, which may be caused by cathepsin B overexpression.

Asunto(s)

Catepsina B/metabolismo , Cardiopatías/metabolismo , Cardiopatías/patología , Mucopolisacaridosis I/metabolismo , Mucopolisacaridosis I/patología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL

RESUMEN

Copaiba oil comes from an Amazonian tree and has been used as an alternative medicine in Brazil. However, it has not been investigated yet in the treatment of cardiovascular diseases. This study was designed to test whether copaiba oil or nanocapsules containing this oil could modulate monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Male Wistar rats (170 ± 20 g) received oil or nanocapsules containing this oil (400 mg/kg) by gavage daily for 1 week. At the end of this period, a single injection of MCT (60 mg/kg i.p.) was administered and measurements were performed after 3 weeks. The animals were divided into 6 groups: control, copaiba oil, nanocapsules with copaiba oil, MCT, oil + MCT, and nanocapsules + MCT. Afterward, echocardiographic assessments were performed, and rats were killed to collect hearts for morphometry and oxidative stress. MCT promoted a significant increase in pulmonary vascular resistance, right ventricle (RV) hypertrophy, and RV oxidative stress. Both oil and copaiba nanocapsules significantly reduced RV hypertrophy and oxidative stress. Pulmonary vascular resistance was reduced by copaiba oil in natura but not by nanocapsules. In conclusion, copaiba oil seems to offer protection against MCT-induced PAH. Our preliminary results suggest that copaiba oil may be an important adjuvant treatment for PAH.

Asunto(s)

Fabaceae , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/tratamiento farmacológico , Monocrotalina/toxicidad , Nanocápsulas/administración & dosificación , Aceites de Plantas/administración & dosificación , Animales , Hipertensión Pulmonar/metabolismo , Masculino , Ratas , Ratas Wistar , Resultado del Tratamiento

RESUMEN

Temporary interruption of enzyme replacement therapy (ERT) in patients with different lysosomal storage disorders may happen for different reasons (adverse reactions, issues with reimbursement, logistic difficulties, and so forth), and the impact of the interruption is still uncertain. In the present work, we studied the effects of the interruption of intravenous ERT (Laronidase, Genzyme) followed by its reintroduction in mice with the prototypical lysosomal storage disorder mucopolysaccharidosis type I, comparing to mice receiving continuous treatment, untreated mucopolysaccharidosis type I mice, and normal mice. In the animals which treatment was temporarily interrupted, we observed clear benefits of treatment in several organs (liver, lung, heart, kidney, and testis) after reintroduction, but a worsening in the thickness of the aortic wall was detected. Furthermore, these mice had just partial improvements in behavioral tests, suggesting some deterioration in the brain function. Despite worsening is some disease aspects, urinary glycosaminoglycans levels did not increase during interruption, which indicates that this biomarker commonly used to monitor treatment in patients should not be used alone to assess treatment efficacy. The deterioration observed was not caused by the development of serum antienzyme antibodies. All together our results suggest that temporary ERT interruption leads to deterioration of function in some organs and should be avoided whenever possible.

Asunto(s)

Terapia de Reemplazo Enzimático , Mucopolisacaridosis I/terapia , Animales , Anticuerpos/sangre , Aorta/patología , Conducta Animal , Encéfalo/patología , Electrocardiografía , Proteína Ácida Fibrilar de la Glía/metabolismo , Glicosaminoglicanos/orina , Pruebas de Función Cardíaca , Ratones , Mucopolisacaridosis I/diagnóstico por imagen , Mucopolisacaridosis I/fisiopatología , Mucopolisacaridosis I/orina

RESUMEN

UNLABELLED: Right ventricle (RV) dysfunction post-myocardial infarction (MI) was associated with a worsened prognosis. In this scenario, reactive oxygen species (ROS) are related with the progression from MI to heart failure. Previous work showed that thyroid hormones (TH) are cardioprotective after MI. AIMS: This study aims to investigate the effect of T3 and T4 administration on oxidative stress and angiogenesis parameters in the RV after MI. MAIN METHODS: Wistar rats were allocated into four groups: Sham-operated (SHAM), infarcted (AMI), sham-operated + TH (SHAMT), and infarcted+TH (AMIT). The treated groups received T3 (2 µg/100g/day) and T4 (8 µg/100g/day) by gavage for 26 days. After this, echocardiographic analysis was performed and the RV was collected to western blot and biochemical analysis. KEY FINDINGS: Infarcted treated rats showed RV hypertrophy compared with AMI and SHAMT. Hydrogen peroxide levels were decrease and SOD activity and expression were increased in the infarcted treated rats. Besides that, the hormonal administration increased eNOS expression and prevented the reduction of VEGF levels in AMIT rats. SIGNIFICANCE: In conclusion, TH seems to improve oxidative stress parameters, to promote physiological hypertrophy and to increase the expression of proteins involved with angiogenesis in the right heart.

Asunto(s)

Infarto del Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Hormonas Tiroideas/uso terapéutico , Remodelación Ventricular/efectos de los fármacos , Animales , Ecocardiografía , Peróxido de Hidrógeno/metabolismo , Hipertrofia Ventricular Derecha/diagnóstico por imagen , Hipertrofia Ventricular Derecha/patología , Neovascularización Patológica/patología , Óxido Nítrico Sintasa de Tipo III/biosíntesis , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Tiroxina/uso terapéutico , Triyodotironina/uso terapéutico

RESUMEN

Apoptosis is a key process associated with pathological cardiac remodelling in early-phase post-myocardial infarction. In this context, several studies have demonstrated an anti-apoptotic effect of thyroid hormones (TH). The aim of this study was to evaluate the effects of TH on the expression of proteins associated with the apoptotic process 14 days after infarction. Male Wistar rats (300-350 g) (n = 8/group) were divided into four groups: Sham-operated (SHAM), infarcted (AMI), sham-operated + TH (SHAMT) and infarcted + TH (AMIT). For 12 days, the animals received T3 and T4 [2 and 8 µg/(100 g day)] by gavage. After this, the rats were submitted to haemodynamic and echocardiographic analysis, and then were sacrificed and the heart tissue was collected for molecular analysis. Statistical analyses included two-way ANOVA with Student-Newman-Keuls post test. Ethics Committee number: 23262. TH administration prevented the loss of ventricular wall thickness and improved cardiac function in the infarcted rats 14 days after the injury. AMI rats presented an increase in the pro-apoptotic proteins p53 and JNK. The hormonal treatment prevented this increase in AMIT rats. In addition, TH administration decreased the Bax:Bcl-2 ratio in the infarcted rats. TH administration improved cardiac functional parameters, and decreased the expression of pro-apoptotic proteins 14 days after myocardial infarction.

Asunto(s)

Proteínas Reguladoras de la Apoptosis/metabolismo , Cardiotónicos/administración & dosificación , Infarto del Miocardio/tratamiento farmacológico , Miocardio/metabolismo , Tiroxina/administración & dosificación , Triyodotironina/administración & dosificación , Animales , Proteínas Reguladoras de la Apoptosis/genética , Cardiotónicos/farmacocinética , Evaluación Preclínica de Medicamentos , Expresión Génica , Peroxidación de Lípido , Masculino , Infarto del Miocardio/metabolismo , Miocardio/patología , Oxidación-Reducción , Estrés Oxidativo , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Tiroxina/farmacocinética , Triyodotironina/farmacocinética , Presión Ventricular/efectos de los fármacos

RESUMEN

UNLABELLED: Myocardial infarction leads to a reduction in nitric oxide (NO) bioavailability and an increase in reactive oxygen species (ROS) levels. This scenario has been shown to be detrimental to the heart. Recent studies have shown that thyroid hormone (TH) administration presents positive effects after ischaemic injury. Based on this, the aim of this study was to evaluate the effect of TH on NO bioavailability as well as on endothelial nitric oxide synthase (eNOS) expression after myocardial infarction. Male Wistar rats were divided into three groups: Sham-operated (SHAM), infarcted (AMI) and infarcted + TH (AMIT). During 26 days, the AMIT group received T3 and T4 (2 and 8 µg/100 g/day, respectively) by gavage, while SHAM and AMI rats received saline. After this, the rats underwent echocardiographic analysis were sacrificed, and the left ventricle was collected for biochemical and molecular analysis. STATISTICAL ANALYSIS: one-way ANOVA with Student-Newman-Keuls post test. AMI rats presented a 38% increase in ROS levels. TH administration prevented these alterations in AMIT rats. The AMIT group presented an increase in eNOS expression, in NOS activity and in nitrite levels. TH administration also increased PGC-1α expression in the AMIT group. In conclusion, TH effects seem to involve a modulation of eNOS expression and an improvement in NO bioavailability in the infarcted heart.

Asunto(s)

Infarto del Miocardio/tratamiento farmacológico , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico/metabolismo , Tiroxina/administración & dosificación , Triyodotironina/administración & dosificación , Animales , Modelos Animales de Enfermedad , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Masculino , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Tiroxina/farmacología , Triyodotironina/farmacología

RESUMEN

Circulating adiponectin has been related to vascular diseases, but few studies examined the relationship between plasma adiponectin and microvascular abnormalities among hypertensive individuals. We tested the association between plasma adiponectin level and retinal vessel calibers in patients with hypertension.This study included 172 patients with confirmed hypertension, aged 18-80 years. Subjects with recent cardiovascular events, advanced heart failure and end-stage renal disease were excluded. Arteriolar and venular calibers were measured in retinographies using a microdensitometric image-processing method. Blood pressure was measured using a validated oscillometric device. We observed a statistically significant inverse association between plasma adiponectin and arteriolar caliber among participants aged 60 years or older after controlling for confounders (Adjusted ß = -0.42; P = .001). In the final model, HbA1C and low-density lipoprotein also remained independently associated with arteriolar caliber. There was no association of adiponectin with venular caliber and retinal vessel calibers in participants <60 years old.Adiponectin is inversely associated with retinal arteriolar caliber in elderly hypertensive participants, suggesting that plasma adiponectin may be a marker of microvascular damage and of higher cardiovascular risk in this age stratum.

Asunto(s)

Adiponectina/sangre , Arteriolas/patología , Hipertensión/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Presión Sanguínea/fisiología , Estudios Transversales , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Vasos Retinianos/patología , Factores de Riesgo , Adulto Joven

RESUMEN

Pulmonary arterial hypertension is characterized by progressive increases in resistance and pressure in the pulmonary artery and Cor pulmonale. The effect of exercise on hydrogen peroxide-dependent signaling in the right ventricle (RV) of Cor pulmonale rats was analyzed. Rats were divided into sedentary control (SC), sedentary monocrotaline (SM), trained control (TC), and trained monocrotaline (TM) groups. Rats underwent exercise training (60% of VO2 max) for 5 weeks, with 3 weeks after monocrotaline injection (60 mg/kg intraperitoneally). Pulmonary resistance was enhanced in SM (2.0-fold) compared with SC. Pulmonary artery pressure was increased in SM (2.7-fold) and TM (2.6-fold) compared with their respective controls (SC and TC). RV hypertrophy indexes increased in SM compared with SC. Hydrogen peroxide was higher in SM (1.7-fold) than SC and was reduced by 47% in TM compared with SM. p-Akt was increased in TM (2.98-fold) compared with SM. The Bax/Bcl-2 ratio and caspase 3 were also increased (2.9-fold and 3.9-fold, respectively) in SM compared with SC. Caspase 3 was decreased in TM compared with SM (P < 0.05). Therefore, exercise training promoted a beneficial response by decreasing hydrogen peroxide concentrations, and consequently, apoptotic signaling in RV.

Asunto(s)

Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis , Hipertrofia Ventricular Derecha/fisiopatología , Condicionamiento Físico Animal/fisiología , Arteria Pulmonar/fisiopatología , Enfermedad Cardiopulmonar/fisiopatología , Animales , Apoptosis/fisiología , Modelos Animales de Enfermedad , Ecocardiografía , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Peróxido de Hidrógeno/metabolismo , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Masculino , Monocrotalina/farmacología , Enfermedad Cardiopulmonar/inducido químicamente , Enfermedad Cardiopulmonar/metabolismo , Enfermedad Cardiopulmonar/patología , Ratas Wistar , Resistencia Vascular/fisiología , Función Ventricular Derecha/efectos de los fármacos , Función Ventricular Derecha/fisiología , Remodelación Ventricular/efectos de los fármacos , Remodelación Ventricular/fisiología

RESUMEN

Mucopolysaccharidosis type I (MPS I) is a progressive disorder caused by deficiency of α-L-iduronidase (IDUA), which leads to storage of heparan and dermatan sulphate. It is suggested that early enzyme replacement therapy (ERT) leads to better outcomes, although many patients are diagnosed late and don't receive immediate treatment. This study aims to evaluate the effects of late onset ERT in a MPS I murine model. MPS I mice received treatment from 6 to 8 months of age (ERT 6-8mo) with 1.2mg laronidase/kg every 2 weeks and were compared to 8 months-old wild-type (Normal) and untreated animals (MPS I). ERT was effective in reducing urinary and visceral GAG to normal levels. Heart GAG levels and left ventricular (LV) shortening fraction were normalized but cardiac function was not completely improved. While no significant improvements were found on aortic wall width, treatment was able to significantly reduce heart valves thickening. High variability was found in behavior tests, with treated animals presenting intermediate results between normal and affected mice, without correlation with cerebral cortex GAG levels. Cathepsin D activity in cerebral cortex also did not correlate with behavior heterogeneity. All treated animals developed anti-laronidase antibodies but no correlation was found with any parameters analyzed. However, intermediary results from locomotion parameters analyzed are in accordance with intermediary levels of heart function, cathepsin D, activated glia and reduction of TNF-α expression in the cerebral cortex. In conclusion, even if started late, ERT can have beneficial effects on many aspects of the disease and should be considered whenever possible.

Asunto(s)

Terapia de Reemplazo Enzimático/métodos , Mucopolisacaridosis I/terapia , Animales , Formación de Anticuerpos , Encéfalo/patología , Catepsina D/metabolismo , Femenino , Glicosaminoglicanos/análisis , Glicosaminoglicanos/orina , Corazón/fisiopatología , Inmunoglobulina G/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Mucopolisacaridosis I/sangre , Mucopolisacaridosis I/fisiopatología , Mucopolisacaridosis I/orina , Miocardio/patología