Efeitos do Óleo de Copaíba em Marcadores Periféricos de Estresse Oxidativo em um Modelo de Cor Pulmonale em Ratos / Effects of Copaiba Oil in Peripheral Markers of Oxidative Stress in a Model of Cor Pulmonale in Rats

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.

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.

Cardiac pathology in mucopolysaccharidosis I mice: Losartan modifies ERK1/2 activation during cardiac remodeling.

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.

Chronic whole-body heat treatment relieves atherosclerotic lesions, cardiovascular and metabolic abnormalities, and enhances survival time restoring the anti-inflammatory and anti-senescent heat shock response in mice.

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.

Copaiba Oil Attenuates Right Ventricular Remodeling by Decreasing Myocardial Apoptotic Signaling in Monocrotaline-Induced Rats.

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.

Effect of Free and Nanoencapsulated Copaiba Oil on Monocrotaline-induced Pulmonary Arterial Hypertension.

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.