Matrix metalloproteinases with gelatinolytic activity induced by Paracoccidioides brasiliensis infection

P>Matrix metalloproteinases (MMPs) modulate extracellular matrix turnover, inflammation and immunity. We studied MMP-9 and MMP-2 in experimental paracoccidioidomycosis. At 15 and 120 days after infection (DAI) with virulent Paracoccidioides brasiliensis, MMP-9 was positive by immunohistochemistry in multinucleated giant cells, in mononuclear cells with macrophage and lymphocyte morphologies and also in fungal cells in the lesions of susceptible and resistant mice. Using gelatin zymography, pro- and active MMP-9 and active MMP-2 were detected in all infected mice, but not in controls. Gelatinolytic activity was not observed in P. brasiliensis extracts. Semiquantitative analysis of gelatinolytic activities revealed weak or absent MMP-2 and strong MMP-9 activity in both mouse strains at 15 DAI, declining at 120 DAI. Avirulent P. brasiliensis-infected mice had residual lesions with MMP-9-positive pseudoxantomatous macrophages, but no gelatinase activity at 120 DAI. Our findings demonstrate the induction of MMPs, particularly MMP-9, in experimental paracoccidioidomycosis, suggesting a possible influence in the pattern of granulomas and in fungal dissemination.

Holter electrocardiography in dogs showing doxorubicin-induced dilated cardiomyopathy

O estudo consistiu na identificação precoce da ocorrência de arritmias em cães com cardiomiopatia dilatada experimental induzida pela doxorrubicina (DOX). Utilizaram-se 10 cães adultos, sadios, distribuídos nos grupos A (n=5) e B (n=5). O grupo B recebeu 30mg/m² de DOX, via intravenosa, a cada 21 dias, até a dose cumulativa de 180 ou 240mg/m². No grupo A (controle), administrou-se solução salina 0,9%, via intravenosa, nos mesmos intervalos do grupo B. Ao se evidenciar o quadro de disfunção miocárdica nos cães do grupo B, caracterizado pela fração de encurtamento menor que 20%, aumento da separação septal do ponto E acima de 0,7cm e aumento do índice volumétrico do ventrículo esquerdo ao final da sístole (61,4ml/m²), realizaram-se os eletrocardiogramas por 24 horas. Os resultados demonstraram aumentos de 44,6% e 41,7% nas freqüências cardíacas mínima e média, respectivamente, e presença, com maior freqüência, de arritmias supraventriculares do que ventriculares nos animais do grupo B. Concluiu-se que o Holter é eficaz e demonstra, com precocidade e melhor definição, as alterações da freqüência e do ritmo cardíaco de cães com disfunção miocárdica induzida pela doxorrubicina.

Energy Expenditure, Lipid Profile, Oxidative Stress, and Cardiac Energy Metabolism After Growth Hormone Treatment in Obese Young Rats

Obesity is rampant in modern society and growth hormone (GH) could be useful as adjunct therapy to reduce the obesity-induced cardiovascular damage. To investigate GH effects on obesity, initially 32 male Wistar rats were divided into two groups (n = 16): control (C) was fed standard-chow and water and hyper-caloric (H) was fed hypercaloric chow and 30% sucrose in its drinking water. After 45 days, both C and H groups were divided into two subgroups (n = 8): C + PL was fed standard-chow, water and received saline subcutaneously; C + GH was fed standard-chow, water, and received 2 mg/kg/day GH subcutaneously; H + PL was fed hypercaloric diet, 30% sucrose in its drinking water, and received saline subcutaneously; and H + GH was fed hypercaloric diet, 30% sucrose in its drinking water, and received GH subcutaneously. After 75 days of total experimental period, H + PL rats were considered obese, having higher body weight, body mass index, Lee-index, and atherogenic index (AI) compared to C + PL. Obesity was accompanied by enhanced myocardial lipid hydroperoxide (LH) and lactate dehydrogenase (LDH), as well of depressed energy expenditure (RMR) and oxygen consumption(VO(2))/body weight. H + GH rats had higher fasting RMR, as well as lower AI and myocardial LH than H + PL. Comparing C + GH with C + PL, despite no effects on morphometric parameters, lipid profile, myocardial LH, and LDH activity, GH enhanced fed RMR and myocardial pyruvate dehydrogenase. In conclusion, the present study brought new insights into the GH effects on obesity related cardiovascular damage demonstrating, for the first time, that GH regulated cardiac metabolic pathways, enhanced energy expenditure and improved the lipid profile in obesity condition. Growth hormone in standard fed condition also offered promising therapeutic value enhancing pyruvate-dehydrogenase activity and glucose oxidation in cardiac tissue, thus optimizing myocardial energy metabolism.

Efeitos do treinamento aeróbio sobre sinais precoces do remodelamento do ventrículo esquerdo induzido pelo diabetes Mellitus experimental

Our aim was to investigate the effects of an aerobic training program on adverse and early left ventricle (LV) remodeling, using an experimental model of short-term type 1 diabetes (T1D). Wistar rats were divided in 4 groups: sedentary control (SC), trained control (TC), sedentary diabetic (SD) and trained diabetic (TD). T1D was induced by streptozotocin (45 mg/kg). The training program consisted of 4 weeks running on a treadmill (13 m/min, 60 min/day, 5 days/week). At the end of the experiments, hearts were collected for analysis of morphology and transcriptional profile of LV, by focusing on its remodeling. Deaths were recorded during the 4-week period. We verified high mortality among animals of DS group, whereas it was significantly reduced in DT group. DS group also showed an increase in cross-sectional area of cardiomyocytes and fibrosis. TD group exhibited reduction in measures of cardiac trophism, but with respect to collagen content, it was similar to CS group. Analysis of gene expression related to cardiac remodeling revealed decreased expression of collagen I and III, as well as low expression of MMP-2 in DS group. TD group showed decreased levels of mRNA for MMP-9, and unchanged gene expression of MMP-2 when compared with the CS group. The expression of MMP-2 and TGF-1 were increased in CT group. The ratio between gene expression of collagen I and III was increased in the CT group and decreased in diabetic groups. These results establish early changes of the structure and transcriptional profile of LV myocardium. Moreover, they indicate that aerobic exercise training plays specific protection against mechanisms responsible for cardiac damage observed in T1D

Auditory stimulation and cardiac autonomic regulation

Previous studies have already demonstrated that auditory stimulation with music influences the cardiovascular system. In this study, we described the relationship between musical auditory stimulation and heart rate variability. Searches were performed with the Medline, SciELO, Lilacs and Cochrane databases using the following keywords: auditory stimulation, autonomic nervous system, music and heart rate variability. The selected studies indicated that there is a strong correlation between noise intensity and vagal-sympathetic balance. Additionally, it was reported that music therapy improved heart rate variability in anthracycline-treated breast cancer patients. It was hypothesized that dopamine release in the striatal system induced by pleasurable songs is involved in cardiac autonomic regulation. Musical auditory stimulation influences heart rate variability through a neural mechanism that is not well understood. Further studies are necessary to develop new therapies to treat cardiovascular disorders.

Down-regulation of the cardiac sarcoplasmic reticulum ryanodine channel in severely food-restricted rats

We have shown that myocardial dysfunction induced by food restriction is related to calcium handling. Although cardiac function is depressed in food-restricted animals, there is limited information about the molecular mechanisms that lead to this abnormality. The present study evaluated the effects of food restriction on calcium cycling, focusing on sarcoplasmic Ca2+-ATPase (SERCA2), phospholamban (PLB), and ryanodine channel (RYR2) mRNA expressions in rat myocardium. Male Wistar-Kyoto rats, 60 days old, were submitted to ad libitum feeding (control rats) or 50% diet restriction for 90 days. The levels of left ventricle SERCA2, PLB, and RYR2 were measured using semi-quantitative RT-PCR. Body and ventricular weights were reduced in 50% food-restricted animals. RYR2 mRNA was significantly decreased in the left ventricle of the food-restricted group (control = 5.92 +/- 0.48 vs food-restricted group = 4.84 +/- 0.33, P < 0.01). The levels of SERCA2 and PLB mRNA were similar between groups (control = 8.38 +/- 0.44 vs food-restricted group = 7.96 +/- 0.45, and control = 1.52 +/- 0.06 vs food-restricted group = 1.53 +/- 0.10, respectively). Down-regulation of RYR2 mRNA expressions suggests that chronic food restriction promotes abnormalities in sarcoplasmic reticulum Ca2+ release.

Tobacco smoke-induced left ventricular remodelling is not associated with metalloproteinase-2 or -9 activation

Aim: To investigate the role of MMP-2 and MMP-9 in cardiac remodelling induced by tobacco smoke exposure in rats.Methods: Rats were allocated into two groups: C (n = 9): control animals; ETS (n = 9): exposed to tobacco smoke. After 4months, the animals underwent echocardiography, morphometric study and determination of MMP-2 and MMP-9 activity.Results: ETS rats had larger diastolic (C= 15.6 +/- 1.2 mm/kg, ETS = 18.0 +/- 0.9 mm/kg; p < 0.001) and systolic (C= 7.3 +/- 1.2 mm/kg, ETS = 9.2 0.9 mm/kg; p = 0.001) ventricular diameters adjusted for body weight. Fractional shortening (C= 53 +/- 4.8%, ETS = 48 +/- 3.3%; p = 0.031) and ejection fraction (C= 0. 89 +/- 0.03 5 ETS = 0. 86 +/- 0.02; p = 0.03 0) were smaller in the ETS group. Myocyte cross-sectional area (C= 245 8 mu m(2), ETS=253 8 mu m(2); p = 0.028) was higher in ETS rats. There were no differences in MNtP-2 (C=50 +/- 14%; ETS 43 +/- 11%, p 0.22 +/- 8) or MMP-9 (C=0.36 +/- 0.3%; ETS=0.62 +/- 0.3%, p=0.630) activity between the groups.Conclusion: MMP-2 and MMP-9 did not participate in the remodelling process induced by tobacco smoke exposure. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Toxicity of dietary restriction of fat enriched diets on cardiac tissue

The present study examines the effects of caloric restriction in cardiac tissue evaluation markers of oxidative stress. High-fat dietary restrictions can have a long-term impact on cardiac health. Dietary restriction of control diet increased myocardial superoxide dismutase (SOD) and catalase activities. Dietary restriction of fatty acid-enriched diets increased myocardial lipoperoxide concentrations, while SOD activity was decreased in cardiac tissue of rats with dietary restriction of fatty acid-enriched diets. Dietary restriction of unsaturated fatty acid-enriched diet induced the highest lipoperoxide concentration and the lowest myocardial SOD activity. Dietary restriction of unsaturated fatty acid decreased myocardial glycogen, and increased the lactate dehydrogenase/citrate synthase ratio. Dietary restriction of fatty acid-enriched diets were more deleterious to cardiac tissue than normal ad lib.-fed diet. In conclusion, the effects of caloric restriction on myocardial oxidative stress is dependent on which nutrient is restricted. Dietary restriction of fatty acid-enriched diets is deleterious relative to ad lib.-fed chow diet. (C) 2002 Elsevier, Science Ltd. All rights reserved.

Myocardial remodeling and dysfunction are induced by chronic food restriction in spontaneously hypertensive rats

Several studies have shown alterations in hearts from animals subjected to food restriction (FR). However, few experiments in hearts evaluating pressure overload have been reported. We examined the effects of chronic FR on myocardial function and morphology in spontaneously hypertensive rats (SHR). Sixty-day-old SHR were fed a control (C) or a restricted diet (daily intake reduced to 50% of amount of food consumed by the control group) for 90 days. Myocardial performance was studied in isolated left ventricular (LV) papillary muscle. Food restriction decreased body weight and LV weight; LV weight/body-weight ratio was lower in the food-restricted group (SHR-C, 2.84 +/- 0.21 mg/g; SHR-FR, 2.56 +/- 0.24 mg/g; P <.05). Food restriction did not change arterial systolic blood pressure. Myocyte surface area was lower in the food-restricted group (P <.01). Food restriction induced myocardial ultrastructural alterations including reduced sarcoplasm content, reduced and disorganized myofilaments, disorganized Z line, dilated sarcoplasmic reticulum, and deep infoldings of plasma membrane. Myocardial hydroxyproline concentration was increased in the restricted rats. Peak developed tension (P <.05) and maximum rate of tension development (P <.01) were decreased in the SHR-FR group. In conclusion, myocardium of SHR subjected to chronic FR presents attenuation of hypertrophy development, ultrastructural changes, increased collagen content, and systolic dysfunction. (c) 2006 Elsevier B.V. All rights reserved.

O bloqueio do sistema renina-angiotensina atenua a remodelação cardíaca de ratos submetidos a estenose aórtica

OBJETIVO: Avaliar o papel do bloqueador dos receptores AT1 e do inibidor da enzima conversora da angiotensina na remodelação cardíaca induzida por estenose aórtica em ratos. MÉTODOS: Ratos Wistar foram divididos em 4 grupos: controle (C, n=13), estenose aórtica (EAo, n=11), EAo com lisinopril, 20 mg/kg/dia (LIS, n=11) e EAo com losartan, 40 mg/kg/dia (LOS, n=9). Os tratamentos foram iniciados 3 dias antes da cirurgia. Após 6 semanas, os animais foram submetidos ao estudo ecocardiográfico, quantificação da concentração de hidroxiprolina e da área seccional (CSA) miocitária do ventrículo esquerdo (VE). RESULTADOS: A EAo induziu aumento da espessura da parede do VE. Os animais LIS e LOS não apresentaram diferença em relação aos animais controles. Os ratos EAo e LIS apresentaram maiores diâmetros do átrio esquerdo que os ratos controles, enquanto nos animais LOS não houve diferença. Os animais com EAo apresentaram maiores valores da porcentagem de encurtamento que os controle. Esse fato não foi modificado com LIS ou LOS. A CSA dos animais do grupo EAo foi maior que a dos controle. Entretanto, o tratamento com LOS e com LIS atenuou o aumento da área induzida pela EAo. A EAo resultou em aumento na concentração de HOP, enquanto o grupo LOS não apresentou diferença em relação ao grupo controle. CONCLUSÃO: O bloqueio do sistema renina-angiotensina, com bloqueador AT1 e com IECA, pode atenuar o desenvolvimento de hipertrofia cardíaca, porém só o bloqueio dos receptores AT1 atenua a fibrose intersticial do VE.

THE ROLE of OXIDATIVE STRESS and LIPID PEROXIDATION IN VENTRICULAR REMODELING INDUCED BY TOBACCO SMOKE EXPOSURE AFTER MYOCARDIAL INFARCTION

OBJECTIVE: To evaluate the roles of oxidative stress and lipid peroxidation in the ventricular remodeling that is induced by tobacco smoke exposure after myocardial infarction.METHODS: After induced myocardial infarction, rats were allocated into two groups: C (control, n=25) and ETS (exposed to tobacco smoke, n=24). After 6 months, survivors were submitted to echocardiogram and biochemical analyses.RESULTS: Rats in the ETS group showed higher diastolic (C = 1.52 +/- 0.4 mm(2), ETS = 1.95 +/- 0.4 mm(2); p=0.032) and systolic (C = 1.03 +/- 0.3, ETS = 1.36 +/- 0.4 mm(2)/g; p=0.049) ventricular areas, adjusted for body weight. The fractional area change was smaller in the ETS group (C = 30.3 +/- 10.1 %, ETS = 19.2 +/- 11.1 %; p=0.024) and E/A ratios were higher in ETS animals (C = 2.3 +/- 2.2, ETS = 5.1 +/- 2.5; p=0.037). ETS was also associated with a higher water percentage in the lung (C = 4.8 (4.3-4.8), ETS = 5.5 (5.3-5.6); p=0.013) as well as higher cardiac levels of reduced glutathione (C = 20.7 +/- 7.6 nmol/mg of protein, ETS = 40.7 +/- 12.7 nmol/mg of protein; p=0.037) and oxidized glutathione (C = 0.3 +/- 0.1 nmol/g of protein, ETS = 0.9 +/- 0.3 nmol/g of protein; p=0.008). No differences were observed in lipid hydroperoxide levels (C = 0.4 +/- 0.2 nmol/mg of tissue, ETS = 0.1 +/- 0.1 nmol/mg of tissue; p=0.08).CONCLUSION: In animals exposed to tobacco smoke, oxidative stress is associated with the intensification of ventricular re-remodeling after myocardial infarction.

Retinoic acid prevents ventricular remodelling induced by tobacco smoke exposure in rats

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Involvement of L-Type Calcium Channel and SERCA2a in Myocardial Dysfunction Induced by Obesity

Obesity has been shown to impair myocardial performance. Nevertheless, the mechanisms underlying the participation of calcium (Ca2+) handling on cardiac dysfunction in obesity models remain unknown. L-type Ca2+ channels and sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a), may contribute to the cardiac dysfunction induced by obesity. The purpose of this study was to investigate whether myocardial dysfunction in obese rats is related to decreased activity and/or expression of L-type Ca2+ channels and SERCA2a. Male 30-day-old Wistar rats were fed standard (C) and alternately four palatable high-fat diets (Ob) for 15 weeks. Obesity was determined by adiposity index and comorbidities were evaluated. Myocardial function was evaluated in isolated left ventricle papillary muscles under basal conditions and after inotropic and lusitropic maneuvers. L-type Ca2+ channels and SERCA2a activity were determined using specific blockers, while changes in the amount of channels were evaluated by Western blot analysis. Phospholamban (PLB) protein expression and the SERCA2a/PLB ratio were also determined. Compared with C rats, the Ob rats had increased body fat, adiposity index and several comorbidities. The Ob muscles developed similar baseline data, but myocardial responsiveness to post-rest contraction stimulus and increased extracellular Ca2+ was compromised. The diltiazem promoted higher inhibition on developed tension in obese rats. In addition, there were no changes in the L-type Ca2+ channel protein content and SERCA2a behavior (activity and expression). In conclusion, the myocardial dysfunction caused by obesity is related to L-type Ca2+ channel activity impairment without significant changes in SERCA2a expression and function as well as L-type Ca2+ protein levels. J. Cell. Physiol. 226: 2934-2942, 2011. (C) 2011 Wiley-Liss, Inc.

Digitalis-Like Induced Arrhythmia in a Patient with Rheumatic Mitral Regurgitation Complicated by Preeclampsia

Objective. To report a case of cardiac arrhythmia related to a low dose of endovenous lanatoside C. Case report. A 23-year-old pregnant woman with mitral regurgitation complicated with preeclampsia and pulmonary edema presented 2 episodes of atrial tachycardia induced by a intravenous digitalis (2 mg, IV and 1 mg, IV, respectively). Conclusion. This case calls attention to the need for further studies analysing the security of digoxin use in preeclampsia.

Coffee and Caffeine Protect against Liver Injury Induced by Thioacetamide in Male Wistar Rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)