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Obesity is a chronic low-grade inflammation condition related to cardiac disorders. However, the mechanism responsible for obesity-related cardiac inflammation is unclear. The toll-like receptor 4 (TLR-4) belongs to a receptor of the transmembrane family responsible for the immune response whose activation stimulates the production of proinflammatory cytokines.To test whether the activation of the TLR-4 receptor participates in the obesity cardiomyopathy process, due to cytokine production through NF-ĸB activation.Male Wistar rats were randomized into two groups: the control group (C, n= 8 animals) that received standard diet/water and the obese group (OB, n= 8 animals) that were fed a high sugar-fat diet and water plus 25% of sucrose for 30 weeks. Nutritional analysis: body weight, adiposity index, food, water, and caloric intake. Obesity-related disorders analysis: plasma glucose, uric acid and triglycerides, HOMA-IR, systolic blood pressure, TNF-α in adipose tissue. Cardiac analysis included: TLR-4 and NF-ĸB protein expression, TNF-α and IL-6 levels. Comparison by unpaired Student's t-test or Mann- Whitney test with a p-value0.05 as statistically significant.The OB group showed obesity, high glucose, triglycerides, uric acid, HOMA, systolic blood pressure, and TNF-α in adipose tissue. OB group presented cardiac remodeling and diastolic dysfunction. TLR-4 and NF-ĸB expression and cytokine levels were higher in OB.Our findings conclude that, in an obesogenic condition, the inflammation derived from cardiac TLR-4 activation can be a mechanism able to lead to remodeling and cardiac dysfunction.A obesidade é uma condição inflamatória crônica de baixo grau relacionada a distúrbios cardíacos. No entanto, o mecanismo responsável pela inflamação cardíaca relacionada à obesidade não é claro. O receptor do tipo toll 4 (TLR-4) pertence a um receptor da família das transmembranas, responsável pela resposta imune, cuja ativação estimula a produção de citocinas pró-inflamatórias.Testar se a ativação do receptor TLR-4 participa do processo de cardiomiopatia da obesidade, devido à produção de citocinas por meio da ativação do NF-ĸB.Ratos Wistar machos foram randomizados em dois grupos: o grupo controle (C, n = 8 animais) que recebeu dieta padrão/água e o grupo obeso (OB, n = 8 animais) que foi alimentado com dieta rica em açúcar e gordura e água mais 25% de sacarose por 30 semanas. Análise nutricional: peso corporal, índice de adiposidade, alimentos, água e ingestão calórica. Análise de distúrbios relacionados à obesidade: glicose plasmática, ácido úrico e triglicerídeos, HOMA-IR, pressão arterial sistólica, TNF-α no tecido adiposo. A análise cardíaca incluiu: expressão das proteínas TLR-4 e NF-ĸB, níveis de TNF-α e IL-6. Comparação pelo teste t de Student não pareado ou teste de Mann-Whitney com um valor de p0,05 como estatisticamente significativo.O grupo OB apresentou obesidade, glicose elevada, triglicerídeos, ácido úrico, HOMA, pressão arterial sistólica e TNF-α no tecido adiposo. O grupo OB apresentou remodelação cardíaca e disfunção diastólica. A expressão de TLR-4 e NF-ĸB e os níveis de citocinas foram maiores em OB.Nossos achados concluem que, em uma condição obesogênica, a inflamação derivada da ativação do TLR-4 cardíaco pode ser um mecanismo capaz de levar à remodelação e disfunção cardíaca.

Made available in DSpace on 2021-06-25T10:46:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The aim of this study is to evaluate whether the alterations in glucose metabolism and insulin resistance are mechanisms presented in cardiac remodelling induced by the toxicity of cigarette smoke. Male Wistar rats were assigned to the control group (C; n = 12) and the cigarette smoke-exposed group (exposed to cigarette smoke over 2 months) (CS; n = 12). Transthoracic echocardiography, blood pressure assessment, serum biochemical analyses for catecholamines and cotinine, energy metabolism enzymes activities assay; HOMA index (homeostatic model assessment); immunohistochemistry; and Western blot for proteins involved in energy metabolism were performed. The CS group presented concentric hypertrophy, systolic and diastolic dysfunction, and higher oxidative stress. It was observed changes in energy metabolism, characterized by a higher HOMA index, lower concentration of GLUT4 (glucose transporter 4) and lower 3-hydroxyl-CoA dehydrogenase activity, suggesting the presence of insulin resistance. Yet, the cardiac glycogen was depleted, phosphofructokinase (PFK) and lactate dehydrogenase (LDH) increased, with normal pyruvate dehydrogenase (PDH) activity. The activity of citrate synthase, mitochondrial complexes and ATP synthase (adenosine triphosphate synthase) decreased and the expression of Sirtuin 1 (SIRT1) increased. In conclusion, exposure to cigarette smoke induces cardiac remodelling and dysfunction. The mitochondrial dysfunction and heart damage induced by cigarette smoke exposure are associated with insulin resistance and glucose metabolism changes. Department of Internal Medicine Botucatu Medical School São Paulo State University-UNESP Faculty of Nutrition UFG – Univ Federal de Goiás Department of Chemical and Biological Sciences São Paulo State University-UNESP Department of Pathology and Legal Medicine Ribeirão Preto Medical School University of São Paulo Experimental Research Unit – UNIPEX Botucatu Medical School São Paulo State University-UNESP Department of Internal Medicine Botucatu Medical School São Paulo State University-UNESP Department of Chemical and Biological Sciences São Paulo State University-UNESP Experimental Research Unit – UNIPEX Botucatu Medical School São Paulo State University-UNESP CAPES: 001 FAPESP: 2014/24197-0 FAPESP: 2016/14547-0 FAPESP: 2016/25676-5

Made available in DSpace on 2021-06-25T10:13:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-01-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background/Aims: Considering the importance of inflammation on obesity-related disorders pathogenesis, including cardiac dysfunction, the interest in natural anti-inflammatory therapeutic strategies has emerged. The lycopene is a carotenoid presents in tomato and red fruits that displays anti-inflammatory properties. In this sense, we will evaluate the anti-inflammatory effect of tomato-oleoresin supplementation on obesity- related cardiac dysfunction by modulating myocardial calcium kinetic. Methods: Male Wistar rats were initially randomized into 2 experimental groups: (Control, n= 20) or high sugar- fat diet (HSF, n=20) for 20 weeks. At week 20th, once detected the cardiac dysfunction (cardiac remodeling, systolic and diastolic dysfunction) by echocardiography in HSF group, animals were randomly divided to begin the treatment with tomato-oleoresin, performing 4 groups: Control (n= 10); Control + tomato tomato-oleoresin supplementation (Control + Ly, n= 10); HSF (n= 10) or HSF + tomato tomato-oleoresin supplementation (HSF + Ly, n= 10). Tomato oleoresin was mixed with maize oil equivalent to 10mg lycopene/kg body weight (BW) per day and given orally, by gavage, every morning for a 10-week period. It was analyzed cardiac inflammatory parameters by the enzyme-linked immunosorbent assay (ELISA) and in vivo (echocardiography) and in vitro (studying isolated papillary muscles from the left ventricle) cardiac function. The groups were compared by Two-Way analysis of variance (ANOVA). Results: The HSF diet induced cardiac dysfunction (FS(%) C: 60.4±1.3; C+Ly: 60.9±1.3; HSF: 51.7±1.3; HSF+Ly: 59.4±1.4) and inflammation (TNF-a: C: 1.88±0.41; C+Ly: 1.93±1.01; HSF: 4.58±1.99; HSF+Ly: 2.03±0.55; IL-6: C: 0.58±0.16; C+Ly: 0.40±0.16; HSF: 2.00±0.45; HSF+Ly: 0.53±0.26; MCP-1: C: 0.31±0.08; C+Ly: 0.43±0.22; HSF: 1.54±0.32; HSF+Ly: 0.50±0.16). Tomato-oleoresin supplementation improved cardiac remodeling and dysfunction, cardiac inflammation and myocardial calcium kinetic. Conclusion: the anti-inflammatory effect of tomato-oleoresin supplementation treated the obesity-induced cardiac dysfunction by modulating myocardial calcium handling. Medical School Sao Paulo State University (UNESP) Institute of Biosciences Sao Paulo State University (UNESP) Medical School Sao Paulo State University (UNESP) Institute of Biosciences Sao Paulo State University (UNESP) FAPESP: 2020/12578-0

Background/aims The beneficial effect of aerobic exercise training (ET) on cardiac remodeling caused by supravalvar aortic stenosis (AS) has been demonstrated in experimental studies; however, the mechanisms responsible for improving cardiac function are not entirely understood. We evaluated whether ET-generated cardioprotection in pressure-overloaded rats is dependent on cardiomyocyte proliferation, increased angiotensin-(1-7) (Ang-1-7) levels, and its receptor in the myocardium. Methods Eighteen weeks after ascending AS surgery, Wistar rats were randomly assigned to four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary aortic stenosis (AS-Sed) and exercised aortic stenosis (AS-Ex) groups. The moderate treadmill exercise protocol was performed for ten weeks. The functional capacity was assessed by treadmill exercise testing. Cardiac structure and function were evaluated by echocardiogram. Cardiomyocyte proliferation was evaluated by flow cytometry. Expression of cell cycle regulatory genes as CCND2, AURKB, CDK1, and MEIS1 was verified by RT-qPCR. Cardiac and plasma angiotensin I (Ang I), angiotensin II (Ang II), and Ang-(1-7) levels were analyzed by high-performance liquid chromatography (HPLC). The angiotensin-converting enzyme (ACE) activity was assessed by the fluorometric method and protein expression of AT1 and Mas receptors by Western blot. Results The AS-Ex group showed reduced left ventricular wall relative thickness and improved ejection fraction; also, it showed decreased gene expression of myocyte cell cycle regulators, ACE, Ang I, Ang II and Ang II/Ang-(1-7) ratio levels compared to AS-Sed group. However, ET did not induce alterations in Ang-(1-7) and cardiac Mas receptor expression and myocyte proliferation. Conclusion Aerobic exercise training improves systolic function regardless of myocyte proliferation and Ang-(1-7)/Mas receptor levels. However, the ET negatively modulates the vasoconstrictor/hypertrophic axis (ACE/Ang II) and decreases the expression of negative regulatory genes of the cell cycle in cardiomyocytes of rats with supravalvular aortic stenosis.

Resumo Fundamento A obesidade tem sido associada com ativação crônica do sistema renina-angiotensina-aldosterona e importantes alterações no desempenho cardíaco. Objetivo Avaliar a influência do bloqueio de receptores de angiotensina-II do tipo 1 (AT1) sobre a morfologia e desempenho cardíaco de ratos obesos por dieta Métodos Ratos Wistar (n=48) foram submetidos a dieta controle (2,9 kcal/g) ou hiperlipídica (3,6 kcal/g) durante 20 semanas. Após a 16ª semana, foram distribuídos em quatro grupos: Controle (CO), Obeso (OB), Controle Losartan (CL) e Obeso Losartan (OL). CL e OL receberam losartan (30 mg/kg/dia) na água durante quatro semanas. Posteriormente, foram analisadas composição corporal, pressão arterial sistólica (PAS) e ecocardiograma. A função de músculos papilares foi avaliada em situação basal com concentração de cálcio ([Ca2+]o) de 2,50 mM e após manobras inotrópicas: potencial pós-pausa (PPP), elevação da [Ca2+]o e durante estimulação beta-adrenérgica com isoproterenol. A análise dos resultados foi feita por meio de Two-Way ANOVA e teste de comparações apropriado. O nível de significância considerado foi de 5%. Resultados Embora a alteração da PAS não tenha se mantido ao final do experimento, a obesidade se associou com hipertrofia cardíaca e maior velocidade de encurtamento da parede posterior do ventrículo esquerdo.No estudo de músculos papilares em condição basal, CL mostrou menor velocidade máxima de variação negativa da tensão desenvolvida (-dT/dt) do que CO. O PPP de 60s promoveu menor -dT/dt e pico de tensão desenvolvida (TD) em OB e CL, comparados ao CO, e maior variação relativa de TD e velocidade máxima de variação positiva (+dT/dt) no OL em relação a CL e OB. Sob 1,5, 2,0 e 2,5mM de [Ca2+]o, o grupo OL exibiu maior -dT/dt do que CL. Conclusão Losartan melhora a função miocárdica de ratos com obesidade induzida por dieta. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0) Abstract Background Obesity has been associated with chronic activation of the renin-angiotensin-aldosterone system and with significant changes in cardiac performance. Objective To assess the impact of a blockade of angiotensin-II receptor type 1 (AT1receptor) on morphology and on myocardial functional performance in rats with high-fat diet- induced obesity. Methods Wistar rats (n=48) were submitted to control (2.9 kcal/g) or high-fat (3.6 kcal/g) diet for 20 weeks. After the 16thweek they were divided into four groups: Control (CO), Obese (OB), Control Losartan (CL) and Obese Losartan (OL). CL and OL received losartan (30 mg/kg/day) in drinking water for four weeks. Subsequently, body composition, systolic blood pressure (SBP) and echocardiographic variables were analyzed. Papillary muscle function was assessed at baseline with 2.50 mM calcium concentration ([Ca2+]o) and after inotropic maneuvers: post-pause potentiation (PPP), [Ca2+]oelevation, and during beta-adrenergic stimulation with isoproterenol. Analysis of the results was performed by the Two-Way ANOVA and by the appropriate comparison test. The level of significance was set at 5%. Results Although SBP change had been not maintained at the end of the experiment, obesity was associated with cardiac hypertrophy and with increased left ventricle posterior wall shortening velocity. In the study of papillary muscles in basal condition, CL showed lower developed tension maximum negative variation velocity (-dT/dt) than CO. The 60s PPP promoted lower -dT/dt and maximum developed tension (DT) in OB and CL compared with CO, and higher relative DT variation and maximum positive variation velocity (+dT/dt) in OL compared with CL and OB. Under 1.5, 2.0, and 2.5mM [Ca2+]o, the OL group showed higher -dT/dt than CL. Conclusion Losartan improves myocardial function in high-fat diet-induced obesity. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

Made available in DSpace on 2020-12-12T01:48:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-12-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Obesity is a pandemic associated with a high incidence of cardiovascular disease; however, the mechanisms are not fully elucidated. Proteomics may provide a more in-depth understanding of the pathophysiological mechanisms and contribute to the identification of potential therapeutic targets. Thus, our study evaluated myocardial protein expression in healthy and obese rats, employing two proteomic approaches. Male Wistar rats were established in two groups (n = 13/group): control diet and Western diet fed for 41 weeks. Obesity was determined by the adipose index, and cardiac function was evaluated in vivo by echocardiogram and in vitro by isolated papillary muscle analysis. Proteomics was based on two-dimensional gel electrophoresis (2-DE) along with mass spectrometry identification, and shotgun proteomics with label-free quantification. The Western diet was efficient in triggering obesity and impaired contractile function in vitro; however, no cardiac dysfunction was observed in vivo. The combination of two proteomic approaches was able to increase the cardiac proteomic map and to identify 82 differentially expressed proteins involved in different biological processes, mainly metabolism. Furthermore, the data also indicated a cardiac alteration in fatty acids transport, antioxidant defence, cytoskeleton, and proteasome complex, which have not previously been associated with obesity. Thus, we define a robust alteration in the myocardial proteome of diet-induced obese rats, even before functional impairment could be detected in vivo by echocardiogram. Department of Internal Medicine Botucatu Medical School São Paulo State University (UNESP) Centre for Proteome Research Institute of Integrative Biology University of Liverpool Liverpool Department of Morphology Institute of Biosciences São Paulo State University (UNESP) Department of Biostatistics Institute of Biosciences São Paulo State University (UNESP) Center for the Study of Venoms and Venomous Animals (CEVAP)/Graduate Program in Tropical Diseases (FMB) São Paulo State University (UNESP) Department of Internal Medicine Botucatu Medical School São Paulo State University (UNESP) Department of Morphology Institute of Biosciences São Paulo State University (UNESP) Department of Biostatistics Institute of Biosciences São Paulo State University (UNESP) Center for the Study of Venoms and Venomous Animals (CEVAP)/Graduate Program in Tropical Diseases (FMB) São Paulo State University (UNESP) FAPESP: 2014/22152-0 FAPESP: 2015/16934-8 FAPESP: 2017/09688-6

Background: The modern dietary habit, which is rich in refined carbohydrates and saturated fats, increases the risk of chronic diseases due to the proinflammatory effect of these nutrients. Aim: To evaluate the impact of high sugar-fat diet in the development of metabolic-inflammatory disorders in non-obese animals. Methods: Male Wistar rats were distributed into two groups according to the diet: control and high sugar-fat for 30 weeks. It was analyzed: dietary efficiency; chow, water and caloric intake; metabolic and hormonal profile in plasma and inflammatory cytokines in epididymal adipose tissue. Data were compared by Student’s t test or by Mann-Whitney U test with p < 0.05 as significant. Results: HSF presented lower chow intake, higher water consumption and dietary efficiency with no difference in the caloric intake. The final body weight (FBW) and weight gain (WG) were lower in the HSF group and there was no difference in the adiposity index (AI). HSF diet-induced hyperglycemia and hyperinsulinemia with no difference for Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Triglycerides, uric acid, adiponectin and leptin levels were higher in the HSF group. The HSF group showed increased interleukin-6 (IL-6) and tumoral necrosis factor-alpha (TNF-α) levels in epidydimal adipose tissue. The urinary protein-creatinine ratio and albuminuria were higher in the HSF group. Conclusion: HSF diet intake is directly involved in the development of metabolic-inflammatory disorders independent of obesity, dissociating the view that increased adiposity is the major risk factor for complications commonly found in obese individuals.

Made available in DSpace on 2022-04-29T08:45:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-06-03 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Universidade Estadual Paulista Aim: To evaluate the influence of physical training on myocardial function, oxidative stress, energy metabolism, and MAPKs and NF-κB signaling pathways in spontaneously hypertensive rats (SHR), at advanced stage of arterial hypertension, which precedes heart failure development. Methods: We studied four experimental groups: normotensive Wistar rats (W, n = 27), trained W (W-EX, n = 31), SHR (n = 27), and exercised SHR (SHR-EX, n = 32). At 13 months old, the exercise groups underwent treadmill exercise 5 days a week for 4 months. In vitro myocardial function was analyzed in left ventricular (LV) papillary muscle preparations. Antioxidant enzyme activity and energy metabolism were assessed by spectrophotometry. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was analyzed by lucigenin reduction and protein expression by Western blot. Statistical analyzes: ANOVA and Tukey or Kruskal–Wallis and Dunn tests. Results: SHR-EX had a lower frequency of heart failure features than SHR. Myocardial function and antioxidant enzyme activity were better in SHR-EX than SHR. Lipid hydroperoxide concentration, and phosphorylated JNK and total IkB protein expression were higher in hypertensive than control groups. Malondialdehyde, NADPH oxidase activity, total JNK, phosphorylated p38, phosphorylated and total p65 NF-κB, and phosphorylated IkB did not differ between groups. Protein expression from total p38, and total and phosphorylated ERK were higher in SHR than W. Lactate dehydrogenase and phosphorylated ERK were lower and citrate synthase and β-hydroxyacyldehydrogenase were higher in SHR-EX than SHR. Conclusion: Exercise improves physical capacity, myocardial function, and antioxidant enzyme activity; reduces the frequency of heart failure features and ERK phosphorylation; and normalizes energy metabolism in SHR. Botucatu Medical School UNESP Sao Paulo State University Itapeva Social and Agrarian Sciences College FAIT Department of Cardiopneumology Medical School University of Sao Paulo (USP) Institute of Biosciences Sao Paulo State University (UNESP) Freshage Research Group Department of Physiology University of Valencia CIBERFES INCLIVA Botucatu Medical School UNESP Sao Paulo State University Institute of Biosciences Sao Paulo State University (UNESP)

Made available in DSpace on 2022-04-29T08:45:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-03-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Purpose: This study aimed to evaluate the effect of rice bran (RB) supplementation to a high-sugar fat (HSF) diet on cardiac dysfunction in an experimental obesity model. Methods: Male Wistar rats were distributed into three groups: control, high-sugar fat, and high-sugar fat supplemented with 11% RB for 20 weeks. Results: HSF diet promoted obesity and metabolic complications. Obese rats showed cardiac structural and functional impairment associated with high levels of interleukin-6, tumoral necrosis factor alpha, and malondialdehyde, and decreased activity of superoxide dismutase and catalase in the myocardium. RB supplementation was able to mitigate obesity and its metabolic alterations in HSF diet-fed animals. Moreover, the RB also prevented structural and functional damage, inflammation, and redox imbalance in the heart of these animals. Conclusion: This study suggests that RB supplementation prevents cardiac dysfunction in rats fed on HSF by modulating systemic metabolic complications and inflammation and oxidative stress in the myocardium, representing potential alternative therapy. São Paulo State University (UNESP) Medical School Department of Biochemistry Institute of Chemistry University of São Paulo (USP) São Paulo State University (UNESP) Institute of Biosciences São Paulo State University (UNESP) Medical School São Paulo State University (UNESP) Institute of Biosciences CNPq: 167750/2018-6 FAPESP: 2018/15294-3

Made available in DSpace on 2021-06-25T15:02:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-04-01 Mato Grosso Research Foundation (FAPEMAT), Brazil Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Background. Decreased cardiac contractility has been observed in cirrhosis, but the mechanisms that initiate and maintain cardiac dysfunction are not entirely understood. Aim of the study. We test the hypothesis that cirrhotic cardiomyopathy is related to deterioration of myocardial contractility due to alterations in calcium-handling proteins expression. In addition, we evaluated whether cardiac pro-inflammatory cytokine levels are associated with this process. Methods. Cirrhosis was induced by thioacetamide (TAA, 100 mg/kg/i.p., twice weekly for eight weeks). The myocardial performance was evaluated in isolated left ventricle papillary muscles under basal conditions and after inotropic challenge. The cardiac calcium handling protein expression was detected by Western blotting. Cardiac TNF-alpha and IL-6 levels were measured by ELISA. Results. Thioacetamide induced liver cirrhosis, which was associated with cirrhotic cardiomyopathy characterized by in vivo left ventricular diastolic and systolic dysfunction as well as cardiac hypertrophy. In vitro baseline myocardial contractility was lower in cirrhosis. Also, myocardial responsiveness to post-rest contraction stimulus was declined. Protein expression for RYR2, SERCA2, NCX, pPBL Ser16 and L-type calcium channel was quantitatively unchanged; however, pPBL Thr17 was significantly lower while IL-6 was higher. Conclusions. Our study demonstrates that cirrhotic cardiomyopathy is associated with decreased cardiac contractility with alteration of phospholamban phosphorylation in association with higher cardiac pro-inflammatory IL-6 levels. These findings provided molecular and functional insights about the effects of liver cirrhosis on cardiac function. (C) 2020 IMSS. Published by Elsevier Inc. Fed Univ Mato Grosso UFMT, Inst Hlth Sci, Ave Alexandre Ferronato 1200, BR-78556267 Sinop, Mato Grosso, Brazil Sao Paulo State Univ, Botucatu Sch Med, Dept Internal Med, Botucatu, SP, Brazil Sao Paulo State Univ, Botucatu Sch Med, Dept Pathol, Botucatu, SP, Brazil Sao Paulo State Univ, Botucatu Sch Med, Dept Internal Med, Botucatu, SP, Brazil Sao Paulo State Univ, Botucatu Sch Med, Dept Pathol, Botucatu, SP, Brazil Mato Grosso Research Foundation (FAPEMAT), Brazil: 161294/2014 CNPq: 442979/2014-2

Background: As some individuals present resistance to obesity development, experiments have been trying to understand their susceptibility to cardiometabolic diseases. Objetive: To evaluate if the cardiac remodeling was related to collagen protein expression change. Methods: Male Wistar rats were randomized into two experimental groups: control diet (CD, n=15) or high-fat diet (HFD, n=15) for 30 weeks. Rats fed with HFD were ranked based on their adiposity indexes and classified as obese (Ob, n = 8) or obesity-resistant (ROb, n = 6). Rats that failed to present the normal characteristic of the control group while fed with CD were excluded (Control, n = 8). Nutritional profile, comorbidities (dyslipidemia, hypertension, glucose metabolism, hyperleptinemia), cardiac remodeling, and collagen protein expression were evaluated. The groups were compared by One-Way ANOVA, together the Tukey post hoc test, with p

Resumo Fundamento A obesidade é um fator de risco para complicações médicas, incluindo o sistema cardiovascular. Há informações limitadas sobre o colágeno no coração obeso. Nosso estudo anterior demonstrou uma redução dos níveis proteicos de colágeno miocárdico tipo I em ratos obesos alimentados com uma dieta com alto teor de gordura durante 34 semanas. No entanto, os mecanismos responsáveis pelos níveis baixos não estão completamente elucidados. Objetivo O objetivo deste estudo foi testar a hipótese de que a redução do colágeno tipo I está associada ao aumento da atividade da metaloproteinase-2 (MMP-2), a qual está ligada à elevação de leptina no miocárdio de ratos obesos. Métodos Ratos Wistar machos com 30 dias de idade foram randomizados em dois grupos: controle (dieta padrão) e obeso (dieta com alto teor de gordura), e alimentados durante 34 semanas. Foram avaliados as características gerais dos animais e os perfis metabólicos e endócrinos. Foram avaliados as expressões proteicas miocárdicas de colágeno tipo I, leptina e inibidores teciduais de metaloproteinases (TIMP), bem como a atividade da MMP-2. O teste de correlação de Pearson foi aplicado para determinar as associações entre variáveis. O nível de significância foi de 5%. Resultados Os animais obesos apresentaram índice de adiposidade mais elevado em comparação ao controle. Foram observadas comorbidades como intolerância à glicose, hiperinsulinemia, resistência à insulina, hiperleptinemia e hipertensão nos ratos obesos. A obesidade reduziu o colágeno tipo I, TIMP-1 e TIMP-2, e aumentou a leptina e a MMP-2 no miocárdio. Houve uma correlação negativa entre o colágeno tipo I e a MMP-2 e uma correlação positiva entre a leptina e a MMP-2. Conclusão Foi confirmada a hipótese de que a redução do colágeno tipo I está associada ao aumento da atividade da MMP-2 e da expressão de leptina no miocárdio de ratos obesos. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0) Abstract Background Obesity is a risk factor for medical complications, including the cardiovascular system. There is limited information on collagen in the heart in obesity. Our previous study showed decreased protein levels of myocardial collagen type I in obese rats fed a high-fat diet for 34 weeks. However, the mechanisms responsible for low levels are not fully elucidated. Objective The purpose of this study was to test the hypothesis that the reduction in collagen type I is associated with increased metalloproteinase-2 (MMP-2) activity, which is linked to elevated leptin in the myocardium of obese rats. Methods Thirty-day-old male Wistar rats were randomized into two groups, control (standard diet) and obese (high-fat diet), and fed for 34 weeks. The general animal characteristics and metabolic and endocrine profiles were evaluated. Myocardial protein expressions of collagen I, leptin, tissue inhibitors of metalloproteinases (TIMP), and MMP-2 activity were assessed. Pearson correlation was employed to determine the associations between variables. The level of significance was 5%. Results The obese animals had increased adiposity index compared to control. Comorbidities such as glucose intolerance, hyperinsulinemia, insulin resistance, hyperleptinemia, and hypertension were observed in obese rats. Obesity reduced collagen I, TIMP-1, and TIMP-2, and it increased leptin and MMP-2 in the myocardium. There was a negative correlation between collagen I and MMP-2 and a positive correlation between leptin and MMP-2. Conclusion The hypothesis was confirmed; the reduction in collagen type I is associated with increased MMP-2 activity and leptin expression in the myocardium of obese rats. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

Made available in DSpace on 2020-12-12T02:14:17Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-01-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Background/Aims: Aortic stenosis-induced chronic pressure overload leads to cardiac dysfunction and congestive heart failure. The pathophysiological mechanisms of the myocardial impairment are multifactorial and include maladaptive β-adrenergic signaling. Exercise training (ET) has been used as a non-pharmacological therapy for heart failure management. The present study tested the hypothesis that exercise training attenuates diastolic dysfunction through β-adrenergic signaling preservation. Methods: Wistar rats were submitted to ascending aortic stenosis (AS) surgery, and after 18 weeks, a moderate aerobic exercise training protocol was performed for ten weeks. Results: ET attenuated diastolic dysfunction, evaluated by echocardiogram and isolated papillary muscle (IPM) assay. Also, ET reduced features of heart failure, cross-sectional cardiomyocyte area, and exercise intolerance, assessed by treadmill exercise testing. The β2 adrenergic receptor protein expression was increased in AS rats independently of exercise. Interestingly, ET restored the protein levels of phosphorylated phospholamban at Serine 16 and preserved the β-adrenergic receptor responsiveness as visualized by the lower myocardial compliance decline and time to 50% tension development and relaxation during β-adrenergic stimulation in the IPM than untrained rats. Additionally, AS rats presented higher levels of TNFα and iNOS, which were attenuated by ET. Conclusion: Moderate ET improves exercise tolerance, reduces heart failure features, and attenuates diastolic dysfunction. In the myocardium, ET decreases the cross-sectional area of the cardiomyocyte and preserves the β-adrenergic responsiveness, which reveals that the adjustments in β-adrenergic signaling contribute to the amelioration of cardiac dysfunction by mild exercise training in aortic stenosis rats. Department of Internal Medicine Botucatu Medical School São Paulo State University Department of Biostatistics Institute of Biosciences of Botucatu São Paulo State University Department of Pathology Botucatu Medical School São Paulo State University Institute of Health Science Federal University of Mato Grosso School of Physical Education and Sport University of São Paulo Department of Internal Medicine Botucatu Medical School São Paulo State University (UNESP) Department of Internal Medicine Botucatu Medical School São Paulo State University Department of Biostatistics Institute of Biosciences of Botucatu São Paulo State University Department of Pathology Botucatu Medical School São Paulo State University Department of Internal Medicine Botucatu Medical School São Paulo State University (UNESP) CAPES: 305399/2015-2 CAPES: 442822/2014-6

// Aline R.R. Lima 1, * , Luana U. Pagan 1, * , Ricardo L. Damatto 1, * , Marcelo D.M. Cezar 1, * , Camila Bonomo 1, * , Mariana J. Gomes 1, * , Paula F. Martinez 2, * , Daniele M. Guizoni 1, * , Dijon H.S. Campos 1, * , Felipe C. Damatto 1, * , Katashi Okoshi 1, * and Marina P. Okoshi 1, * 1 Botucatu Medical School, Internal Medicine Departament, Sao Paulo State University, UNESP, Botucatu, Brazil 2 School of Physical Therapy, Federal University of Mato Grosso do Sul, Campo Grande, Brazil * These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation Correspondence to: Marina P. Okoshi, email: mpoliti@fmb.unesp.br Keywords: heart failure, skeletal muscle, growth hormone, muscle trophicity, satellite cells Received: March 28, 2017 Accepted: July 29, 2017 Published: August 24, 2017 ABSTRACT Background: Skeletal muscle wasting is often observed in heart failure (HF). The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis is impaired in HF. In this study, we evaluated the effects of GH on soleus muscle and cardiac remodeling in rats with aortic stenosis (AS)-induced HF. Methods: AS was created by placing a stainless-steel clip on the ascending aorta. After clinically detecting HF, GH (2 mg/kg/day) was subcutaneously injected for 14 days (AS-GH group). Results were compared with those from Sham and non-treated AS groups. Transthoracic echocardiogram was performed before and after treatment. Protein expression was evaluated by Western blot and satellite cells activation by immunofluorescence. Statistical analyzes: ANOVA and Tukey or Kruskal-Wallis and Student-Newman-Keuls. Results: Before treatment both AS groups presented a similar degree of cardiac injury. GH prevented body weight loss and attenuated systolic dysfunction. Soleus cross-sectional fiber areas were lower in both AS groups than Sham (Sham 3,556±447; AS 2,882±422; AS-GH 2,868±591 μm 2 ; p=0.016). GH increased IGF-1 serum concentration (Sham 938±83; AS 866±116; AS-GH 1167±166 ng/mL; p

Made available in DSpace on 2022-04-29T08:27:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-12-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background: The aim of this study is to test the hypothesis that obesity induced by a diet rich in saturated fats and balanced in carbohydrates is associated with the development of systemic complications and comorbidities. Methods: Thirty-seven 60-day-old male Wistar rats were randomized into two groups: control (C, n = 18, standard diet) and obese (OB, n = 19, high-saturated fat diet), for 33 weeks. Nutritional profile: food and caloric intake, feed efficiency, body weight, and adiposity index. Complications: in plasma were analyzed dyslipidemia, insulin resistance (HOMA-IR), glucose intolerance, hyperleptinemia, hyperinsulinemia, plasmatic C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α); in the myocardial and epididymal adipose tissue were assessed IL-6 and TNF-α. Comorbidities: diabetes mellitus and systemic blood pressure (SBP). Student’s t test, ANOVA, and Bonferroni P < 0.05. Results: The final body weight, feed efficiency, and adiposity index were higher in OB group than in control; although food intake was lower in OB group, caloric intake was similar in both groups. Specific parameters, such as LDL, cholesterol, triglycerides, HOMA-IR, CRP, TNF-α in epididymal adipose tissue, and IL-6 in the myocardium, were higher in obese rats than in controls. SBP, baseline glucose, and glucose after 2 h of overload were significantly increased in OB group; however, the severity was not enough to classify the animals as diabetic and hypertensive. Conclusion: Obesity induced by a diet high in saturated fatty acids with balanced carbohydrates for 33 weeks in Wistar rats was effective in triggering complications but unable to develop comorbidities. Department of Internal Medicine Botucatu Medical School São Paulo State University Department of Pathology Botucatu School of Medicine São Paulo State University–UNESP, Distrito de Rubião Jr s/n Department of Biostatistics Botucatu Biosciences Institute São Paulo State University Department of Biochemistry Botucatu Biosciences Institute São Paulo State University Department of Internal Medicine Botucatu Medical School São Paulo State University Department of Pathology Botucatu School of Medicine São Paulo State University–UNESP, Distrito de Rubião Jr s/n Department of Biostatistics Botucatu Biosciences Institute São Paulo State University Department of Biochemistry Botucatu Biosciences Institute São Paulo State University FAPESP: 2012/25094-5

Made available in DSpace on 2018-12-11T17:17:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-01-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Background/Aims: To evaluate the effects of the antioxidant N-acetylcysteine (NAC) on cardiac structure and function in rats with long-term ascending aortic stenosis (AS). Methods: Four months after inducing AS, Wistar rats were assigned into the groups Sham, AS, and AS treated with NAC (AS-NAC) and followed for eight weeks. Cardiac structure and function were evaluated by echocardiogram. Myocardial antioxidant enzymes activity was measured by spectrophotometry and malondialdehyde serum concentration by HPLC. Gene expression of NADPH oxidase subunits NOX2, NOX4, p22 phox, and p47 phox was assessed by real time RT-PCR and protein expression of MAPK proteins by Western blot. Statistical analyzes were performed with Goodman and ANOVA or Mann-Whitney Results: NAC restored myocardial total glutathione (Sham 20.8±3.00; AS 12.6±2.92; AS-NAC 17.6±2.45 nmol/g tissue; p

The system redox imbalance is one of the pathways related to obesity-related cardiac dysfunction. Lycopene is considered one of the best antioxidants. The aim of this study was to test if the tomato-oleoresin would be able to recovery cardiac function by improving &beta, adrenergic response due its antioxidant effect. A total of 40 animals were randomly divided into two experimental groups to receive either the control diet (Control, n = 20) or a high sugar-fat diet (HSF, n = 20) for 20 weeks. Once cardiac dysfunction was detected by echocardiogram in the HSF group, animals were re- divided to begin the treatment with Tomato-oleoresin or vehicle, performing four groups: Control (n = 6), (Control + Ly, n = 6), HSF (n = 6) and (HSF + Ly, n = 6). Tomato oleoresin (10 mg lycopene/kg body weight (BW) per day) was given orally every morning for a 10-week period. The analysis included nutritional and plasma biochemical parameters, systolic blood pressure, oxidative parameters in plasma, heart, and cardiac analyses in vivo and in vitro. A comparison among the groups was performed by two-way analysis of variance (ANOVA). Results: The HSF diet was able to induce obesity, insulin-resistance, cardiac dysfunction, and oxidative damage. However, the tomato-oleoresin supplementation improved insulin-resistance, cardiac remodeling, and dysfunction by improving the &beta, adrenergic response. It is possible to conclude that tomato-oleoresin is able to reduce the oxidative damage by improving the system&rsquo, s &beta, adrenergic response, thus recovering cardiac function.

Severe food restriction (FR) impairs cardiac performance, although the causative mechanisms remain elusive. Since proteins associated with calcium handling may contribute to cardiac dysfunction, this study aimed to evaluate whether severe FR results in alterations in the expression and activity of Ca2+-handling proteins that contribute to impaired myocardial performance. Male 60-day-old Wistar&ndash, Kyoto rats were fed a control or restricted diet (50% reduction in the food consumed by the control group) for 90 days. Body weight, body fat pads, adiposity index, as well as the weights of the soleus muscle and lung, were obtained. Cardiac remodeling was assessed by morphological measures. The myocardial contractile performance was analyzed in isolated papillary muscles during the administration of extracellular Ca2+ and in the absence or presence of a sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) specific blocker. The expression of Ca2+-handling regulatory proteins was analyzed via Western Blot. Severe FR resulted in a 50% decrease in body weight and adiposity measures. Cardiac morphometry was substantially altered, as heart weights were nearly twofold lower in FR rats. Papillary muscles isolated from FR hearts displayed mechanical dysfunction, including decreased developed tension and reduced contractility and relaxation. The administration of a SERCA2a blocker led to further decrements in contractile function in FR hearts, suggesting impaired SERCA2a activity. Moreover, the FR rats presented a lower expression of L-type Ca2+ channels. Therefore, myocardial dysfunction induced by severe food restriction is associated with changes in the calcium-handling properties in rats.

Made available in DSpace on 2021-06-25T10:57:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-06-01 Metabolic syndrome (MetS) include obesity as a critical feature and is strongly associated with risk of cardiovascular disease (CVD). Insights into mechanisms involved in the pathophysiology of these clinical manifestations are essential for the development of therapeutic strategies. Thus, Western diets (WD) have been widely employed in diet-induced obesity (DIO) model. However, there are variations in fat and sugar proportions of such diets, making comparisons challenging. We aimed to assess the impact of two types of the WD on metabolic status and cardiac remodeling, to achieve a DIO model that better mimics the human pathogenesis of MetS-induced CVD. Male Wistar rats were distributed into three groups: control diet, Western diet fat (WDF), and Western diet sugar (WDS) for 41 weeks. Metabolic and inflammatory parameters and cardiac changes were characterized. WDF and WDS feeding promoted higher serum triglycerides, glucose intolerance, and insulin resistance, while just WDF presented inflammation in adipose tissue. WDF-fed rats showed increased catalase activity and malondialdehyde (MDA) and carbonyl protein levels, suggesting cardiac oxidative stress, while WDS-fed rats only raised MDA. Both WD equally elevated protein expressions involved in lipid metabolism, but only WDF downregulated the glycolysis pathway. Furthermore, the mechanical myocardial function was impaired in obese rats, being more relevant in WDF. In conclusion, both WD effectively triggered MetS features, although inflammation was detected just on the WDF-fed animals. Moreover, the WDF promoted a more pronounced functional, metabolic, and oxidative cardiac disorder, suggesting to be an adequate model for studying CVD in the scenario of MetS. Department of Internal Medicine Botucatu Medical School São Paulo State University (UNESP) Department of Patology Botucatu Medical School São Paulo State University (UNESP) Department of Biostatistics Institute of Biosciences São Paulo State University (UNESP) Department of Internal Medicine Botucatu Medical School São Paulo State University (UNESP) Department of Patology Botucatu Medical School São Paulo State University (UNESP) Department of Biostatistics Institute of Biosciences São Paulo State University (UNESP)

Made available in DSpace on 2018-12-11T17:08:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-01-01. Added 1 bitstream(s) on 2019-10-09T18:30:42Z : No. of bitstreams: 1 S2359-39972016000600582.pdf: 208346 bytes, checksum: d4024e8a967f9479c5370d43b346a841 (MD5) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Objective: The current study was aimed at analyzing sarcoplasmic reticulum Ca2+ ATPase (Serca2) and ryanodine receptor type 2 (Ryr2) gene expression in rats subjected to surgery that induced HF and were subsequently treated with T4 using physiological doses. Materials and methods: HF was induced in 18 male Wistar rats by clipping the ascending thoracic aorta to generate aortic stenosis (HFS group), while the control group (9-sham) underwent thoracotomy. After 21 weeks, the HFS group was subdivided into two subgroups. One group (9 Wistar rats) with HF received 1.0 µg of T4/100 g of body weight for five consecutive days (HFS/T4); the other group (9 Wistar rats) received isotonic saline solution (HFS/S). The animals were sacrificed after this treatment and examined for signs of HF. Samples from the left ventricles of these animals were analyzed by RT-qPCR for the expression of Serca2 and Ryr2 genes. Results: Rats with HF developed euthyroid sick syndrome (ESS) and treatment with T4 restored the T3 values to the Sham level and increased Serca2 and Ryr2 gene expression, thereby demonstrating a possible benefit of T4 treatment for heart function in ESS associated with HF. Conclusion: The T4 treatment can potentially normalize the levels of T3 as well elevated Serca2 and Ryr2 gene expression in the myocardium in heart failure rats with euthyroid sick syndrome. Departamento de Clínica Médica Unidade de Pesquisa Experimental (Unipex) Faculdade de Medicina de Botucatu Universidade Estadual Paulista (Unesp) Instituto de Ciências da Saúde Universidade Federal de Mato Grosso (UFMT) Departamento de Bioestatística Instituto de Biociências Universidade Estadual Paulista (Unesp) Departamento de Clínica Médica Unidade de Pesquisa Experimental (Unipex) Faculdade de Medicina de Botucatu Universidade Estadual Paulista (Unesp) Departamento de Bioestatística Instituto de Biociências Universidade Estadual Paulista (Unesp) FAPESP: 2007/55902-8

New Findings What is the central question of this study? We investigated the effects of physical training on phenotypic (fibre-type content) and myogenic features (MyoD and myogenin expression) in skeletal muscle during the transition from cardiac hypertrophy to heart failure. What is the main finding and its importance? We provide new insight into skeletal muscle adaptations by showing that physical training increases the type I fibre content during the transition from cardiac hypertrophy to heart failure, without altering MyoD and myogenin expression. These results have important clinical implications for patients with heart failure, because this population has reduced muscle oxidative capacity. The purpose of this study was to investigate the effects of physical training (PT) on phenotypic features (fibre-type content) and myogenic regulatory factors (MyoD and myogenin) in rat skeletal muscle during the transition from cardiac hypertrophy to heart failure. We used the model of ascending aortic stenosis (AS) to induce heart failure in male Wistar rats. Sham-operated animals were used as age-matched controls. At 18 weeks after surgery, rats with ventricular dysfunction were randomized into the following four groups: sham-operated, untrained (Sham-U; n = 8); sham-operated, trained (Sham-T; n = 6); aortic stenosis, untrained (AS-U; n = 6); and aortic stenosis, trained (AS-T; n = 8). The AS-T and Sham-T groups were submitted to a 10 week aerobic PT programme, while the AS-U and Sham-U groups remained untrained for the same period of time. After the PT programme, the animals were killed and the soleus muscles collected for phenotypic and molecular analyses. Physical training promoted type IIa-to-I fibre conversion in the trained groups (Sham-T and AS-T) compared with the untrained groups (Sham-U and AS-U). No significant (P > 0.05) differences were found in type I or IIa fibre content in the AS-U group compared with the Sham-U group. Additionally, there were no significant (P > 0.05) differences in the myogenic regulatory factors MyoD and myogenin (gene and protein) expression between the groups. Therefore, our results indicate that PT may be a suitable strategy to improve the oxidative phenotype in skeletal muscle during the transition from cardiac hypertrophy to heart failure, without altering MyoD and myogenin.

Made available in DSpace on 2022-04-29T08:27:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-12-01 Cardiac remodeling (CR) is a structural change of the heart due to chronic hemodynamic overload related to changes in both myocyte and extracellular matrix (ECM). We investigated that the imbalance of collagen V promotes cardiomyocyte apoptosis that contributes to heart failure and cell death. Aortic stenosis was induced surgically and male Wistar rats were randomized to 18 weeks (Sham 18 w, n = 12; AoS 18 w, n = 12) and severe of heart failure (Sham HF, n = 12; AoS HF, n = 12) groups. Functional and structural echocardiogram, immunohistochemistry for Ki-67, TUNEL assay and Immunofluorescence for collagen were performed. Our main results were: (1) Progressive reduction of cardiac functional capacity due to cardiac remodeling with decreased eject fraction in heart failure; (2) Imbalance of collagen deposition with increased, crowded and irregular collagen I in situ expression; (3) Dysregulation of dynamic control of collagen fibers with exposed epitopes of collagen V; (4) Additional apoptosis that are dependent to cardiac injury. The collagen V expression in cardiac remodeling is for the first time described and may be related to additional apoptosis and autoimmune response. Our findings suggest a critical role of collagen V in cardiac remodeling to modulate and promote heart failure and death. Department of Internal Medicine Botucatu Medical School São Paulo State University Department of Pathology and Legal Medicine Ribeirão Preto Medical School University of São Paulo Department of Pathology Faculty of Medicine University of São Paulo Department of Internal Medicine Botucatu Medical School São Paulo State University

Made available in DSpace on 2015-12-07T15:31:24Z (GMT). No. of bitstreams: 0 Previous issue date: 2015. Added 1 bitstream(s) on 2015-12-07T15:54:08Z : No. of bitstreams: 1 S0102-86502015000700484.pdf: 443014 bytes, checksum: 819306b4d423c3f330eb6c85771bb2ac (MD5) To study racemic bupivacaine, non-racemic bupivacaine and ropivacaine on myocardial contractility. Isolated Wistar papillary muscles were submitted to 50 and 100 mM racemic bupivacaine (B50 and B100), non-racemic bupivacaine (NR50 and NR100) and ropivacaine (R50 and R100) intoxication. Isometric contraction data were obtained in basal condition (0.2 Hz), after increasing the frequency of stimulation to 1.0 Hz and after 5, 10 and 15 min of local anesthetic intoxication. Data were analyzed as relative changes of variation. Developed tension was higher with R100 than B100 at D1 (4.3 ± 41.1 vs -57.9 ± 48.1). Resting tension was altered with B50 (-10.6 ± 23.8 vs -4.7 ± 5.0) and R50 (-14.0 ± 20.5 vs -0.5 ± 7.1) between D1 and D3. Maximum rate of tension development was lower with B100 (-56.6 ± 38.0) than R50 (-6.3 ± 37.9) and R100 (-1.9 ± 37.2) in D1. B50, B100 and NR100 modified the maximum rate of tension decline from D1 through D2. Time to peak tension was changed with NR50 between D1 and D2. Racemic bupivacaine depressed myocardial contractile force more than non-racemic bupivacaine and ropivacaine. Non-racemic and racemic bupivacaine caused myocardial relaxation impairment more than ropivacaine. Universidade Estadual Paulista, Departamento de Anestesiologia, Faculdade de Medicina de Botucatu Universidade Estadual Paulista, Departamento de Clínica Médica, Faculdade de Medicina de Botucatu

Made available in DSpace on 2015-12-07T15:31:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2015. Added 1 bitstream(s) on 2015-12-07T15:52:34Z : No. of bitstreams: 1 PMC4609864.pdf: 1437164 bytes, checksum: 4ac08666cb65268ebe8ec0a7a2e538ae (MD5) We evaluated the effects of a low intensity aerobic exercise protocol on cardiac remodeling and myocardial function in diabetic rats. Wistar rats were assigned into four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary diabetes (DM-Sed), and exercised diabetes (DM-Ex). Diabetes was induced by intraperitoneal injection of streptozotocin. Rats exercised for 9 weeks in treadmill at 11 m/min, 18 min/day. Myocardial function was evaluated in left ventricular (LV) papillary muscles and oxidative stress in LV tissue. Statistical analysis was given by ANOVA or Kruskal-Wallis. Echocardiogram showed diabetic groups with higher LV diastolic diameter-to-body weight ratio and lower posterior wall shortening velocity than controls. Left atrium diameter was lower in DM-Ex than DM-Sed (C-Sed: 5.73 ± 0.49; C-Ex: 5.67 ± 0.53; DM-Sed: 6.41 ± 0.54; DM-Ex: 5.81 ± 0.50 mm; P < 0.05 DM-Sed vs C-Sed and DM-Ex). Papillary muscle function was depressed in DM-Sed compared to C-Sed. Exercise attenuated this change in DM-Ex. Lipid hydroperoxide concentration was higher in DM-Sed than C-Sed and DM-Ex. Catalase and superoxide dismutase activities were lower in diabetics than controls and higher in DM-Ex than DM-Sed. Glutathione peroxidase activity was lower in DM-Sed than C-Sed and DM-Ex. Conclusion. Low intensity exercise attenuates left atrium dilation and myocardial oxidative stress and dysfunction in type 1 diabetic rats. Department of Internal Medicine, Botucatu Medical School, São Paulo State University (UNESP), S/N, Rubião Junior District, 18618 970 Botucatu, SP, Brazil ; Sagrado Coração University, Bauru, SP, Brazil. Department of Internal Medicine, Botucatu Medical School, São Paulo State University (UNESP), S/N, Rubião Junior District, 18618 970 Botucatu, SP, Brazil. Department of Chemistry and Biochemistry, Institute of Biosciences, São Paulo State University (UNESP), Brazil. Department of Internal Medicine, Botucatu Medical School, São Paulo State University (UNESP), S/N, Rubião Junior District, 18618 970 Botucatu, SP, Brazil ; Sagrado Coração University, Bauru, SP, Brazil. Department of Internal Medicine, Botucatu Medical School, São Paulo State University (UNESP), S/N, Rubião Junior District, 18618 970 Botucatu, SP, Brazil. Department of Chemistry and Biochemistry, Institute of Biosciences, São Paulo State University (UNESP), Brazil.

Made available in DSpace on 2018-12-11T17:35:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-12-01 Made available in DSpace on 2018-12-11T17:35:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-12-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background: The high consumption of fat and sugar contributes to the development of obesity and co-morbidities, such as diabetes, and cardiovascular and kidney diseases. Different strategies have been used to prevent these diseases associated with obesity, such as changes in eating habits and/or the addition of dietary components with anti-inflammatory and anti-oxidant properties, such as gamma-oryzanol (γQz) present mainly in bran layers and rice germ. Methods: Animals were randomly divided into four experimental groups and fed ad libitum for 20 weeks with control diet (C, n = 8), control diet + γOz (C + yOz, n = 8), high-sugar and high-fat diet (HSF, n = 8), and high-sugar and high-fat diet + γOz (HSF + γOz, n = 8). HSF groups also received water + sucrose (25%). The dose of γOz was added to diets to reach 0.5% of final concentration (w/w). Evaluation in animals included food and caloric intake, body weight, plasma glucose, insulin, triglycerides, uric acid, HOMA-IR, glomerular filtration rate, protein/creatinine ratio, systolic blood pressure, and Doppler echocardiographic. Results: Animals that consumed the HSF diet had weight gain compared to group C, increased insulin, HOMA, glucose and triglycerides, there were also atrial and ventricular structural alterations, deterioration of systolic and diastolic function, decreased glomerular filtration rate, and proteinuria. Gamma-oryzanol is significantly protective against effects on body weight, hypertriglyceridemia, renal damage, and against structural and functional alteration of the heart. Conclusion: Gamma-oryzanol shows potential as a therapeutic to prevent Cardiorenal Metabolic Syndrome. São Paulo State University (Unesp) Medical School São Paulo State University (Unesp) Institute of Biosciences São Paulo State University (Unesp) Medical School São Paulo State University (Unesp) Institute of Biosciences FAPESP: 2015/10626-0

Background: Different types of high-fat and/or high-energy diets have been used to induce obesity in rodents. However, few studies have reported on the effects observed at the initial stage of obesity induced by high-fat feeding on cardiac functional and structural remodelling. Objective: To characterize the initial moment of obesity and investigate both metabolic and cardiac parameters. In addition, the role of Ca2+ handling in short-term exposure to obesity was verified. Methods: Thirty-day-old male Wistar rats were randomized into two groups (n = 19 each): control (C; standard diet) and high-fat diet (HF, unsaturated high-fat diet). The initial moment of obesity was defined by weekly measurement of body weight (BW) complemented by adiposity index (AI). Cardiac remodelling was assessed by morphological, histological, echocardiographic and papillary muscle analysis. Ca2+ handling proteins were determined by Western Blot. Results: The initial moment of obesity occurred at the 3rd week. Compared with C rats, the HF rats had higher final BW (4%), body fat (20%), AI (14.5%), insulin levels (39.7%), leptin (62.4%) and low-density lipoprotein cholesterol (15.5%) but did not exhibit alterations in systolic blood pressure. Echocardiographic evaluation did not show alterations in cardiac parameters. In the HF group, muscles were observed to increase their +dT/dt (C: 52.6 ± 9.0 g/mm2/s and HF: 68.0 ± 17.0 g/mm2/s; p < 0.05). In addition, there was no changes in the cardiac expression of Ca2+ handling proteins. Conclusion: The initial moment of obesity promotes alterations to hormonal and lipid profiles without cardiac damage or changes in Ca2+ handling. Resumo Fundamentos: Diferentes tipos de dietas hiperlipídicas e/ou hipercalóricas têm sido usados para induzir obesidade em roedores. No entanto, poucos estudos relataram os efeitos da obesidade induzida por dieta hiperlipídica em sua fase inicial sobre a remodelação cardíaca funcional e estrutural. Objetivo: Caracterizar o momento inicial da obesidade e investigar parâmetros metabólicos e cardíacos. Além disso, analisar o papel do trânsito de Ca+2 em curtos períodos de exposição à obesidade. Métodos: Ratos Wistar com idade de 30 dias foram distribuídos aleatoriamente em dois grupos (n = 19 em cada grupo): controle (C, dieta padrão) e dieta hiperlipídica (HL, dieta rica em gordura insaturada). O momento inicial da obesidade foi definido por medidas semanais do peso corporal, complementadas pelo índice de adiposidade (IA). A remodelação cardíaca foi avaliada por análise morfológica, histológica, ecocardiográfica e funcional dos músculos papilares. Proteínas envolvidas no trânsito de Ca2+ foram determinadas por Western Blot. Resultados: O momento inicial da obesidade ocorreu na terceira semana. Em comparação aos ratos C, os animais HL apresentaram maior peso corporal final (4%), gordura corporal (20%), IA (14,5%), níveis de insulina (39,7%), leptina (62,4%) e lipoproteína de baixa densidade (15,5%), mas não apresentaram alterações na pressão sistólica. A avaliação ecocardiográfica não mostrou alterações nos parâmetros cardíacos. No grupo HL, observou-se um aumento no +dT/dt (C: 52,6 ± 9,0 g/mm2/s e HL: 68,0 ± 17,0 g/mm2/s; p < 0,05) muscular. Além disso, não houve alterações na expressão cardíaca de proteínas envolvidas no trânsito de Ca2+. Conclusão: O momento inicial da obesidade promove alterações nos perfis hormonais e lipídicos sem causar danos cardíacos ou mudanças no trânsito de Ca2+.

Made available in DSpace on 2018-11-26T17:42:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-10-01 Fundacao de Amparo a Pesquisa e Inovacao do Estado do Espirito Santo (FAPES), Vitoria, ES, Brazil Authors have showed that obesity implicates cardiac dysfunction associated with myocardial L-type calcium channels (LTCCs) activity impairments, as well as moderate exercise training (MET) seems to be an important therapeutic tool. We tested the hypothesis that MET promotes improvements on LTCCS activity and protein expression at obesity induced by unsaturated high-fat diets, which could represent a protective effects against development of cardiovascular damage. Male Wistar rats were randomized in control (C, n = 40), which received a standard diet and obese (Ob; n = 40), which received high-fat diet. After 20 weeks, the animals were assigned at four groups: control (C; n = 12); control submitted to exercise training (ET; n = 14); obese (Ob; n = 10); and obese submitted to exercise training (ObET; n = 11). ET (5 days/week during 12 weeks) began in the 21th week and consisted of treadmill running that was progressively increased to reach 60 min. Final body weight (FBW), body fat (BF), adiposity index (AI), comorbidities, and hormones were evaluated. Cardiac remodeling was assessed by morphological and isolated papillary muscles function. LTCCs activity was determined using specific blocker, while protein expression of LTCCs was evaluated by Western blot. Unsaturated high-fat diet promoted obesity during all experimental protocol. MET controlled obesity process by decreasing of FBW, BF, and AI. Obesity implicated to LTCCs protein expression reduction and MET was not effective to prevent this condition. ET was efficient to promote several improvements to body composition and metabolic parameters; however, it was not able to prevent or reverse the downregulation of LTCCs protein expression at obese rats. Sao Paulo State Univ, Dept Internal Med, Botucatu, SP, Brazil Univ Fed Espirito Santo, Dept Sports, Ctr Phys Educ & Sports, Vitoria, ES, Brazil Sao Paulo State Univ, Dept Morphol, Botucatu, SP, Brazil Sao Paulo State Univ, Inst Biosci, Dept Biostat, Botucatu, SP, Brazil Univ Fed Mato Grosso, Inst Hlth Sci, Sinop, Brazil Sao Paulo State Univ, Dept Internal Med, Botucatu, SP, Brazil Sao Paulo State Univ, Dept Morphol, Botucatu, SP, Brazil Sao Paulo State Univ, Inst Biosci, Dept Biostat, Botucatu, SP, Brazil Fundacao de Amparo a Pesquisa e Inovacao do Estado do Espirito Santo (FAPES), Vitoria, ES, Brazil: 67633269/15

Background: The higher consumption of fat and sugar are associated with obesity development and its related diseases such as non-alcoholic fatty liver disease (NAFLD). Lycopene is an antioxidant whose protective potential on fatty liver degeneration has been investigated. The aim of this study was to present the therapeutic effects of lycopene on NAFLD related to the obesity induced by a hypercaloric diet. Methods: Wistar rats were distributed in two groups: Control (Co, n = 12) and hypercaloric (Ob, n = 12). After 20 weeks, the animals were redistributed into the control group (Co, n = 6), control group supplemented with lycopene (Co+Ly, n = 6), obese group (Ob, n = 6), and obese group supplemented with lycopene (Ob+Ly, n = 6). Ob groups also received water + sucrose (25%). Animals received lycopene solution (10 mg/kg/day) or vehicle (corn oil) via gavage for 10 weeks. Results: Animals which consumed the hypercaloric diet had higher adiposity index, increased fasting blood glucose, hepatic and blood triglycerides, and also presented in the liver macro and microvesicular steatosis, besides elevated levels of tumor necrosis factor-&alpha, (TNF-&alpha, ). Lycopene has shown therapeutic effects on blood and hepatic lipids, increased high-density lipoprotein cholesterol (HDL), mitigated TNF-&alpha, and malondialdehyde (MDA) and further improved the hepatic antioxidant capacity. Conclusion: Lycopene shows therapeutic potential to NAFLD.

Made available in DSpace on 2014-12-03T13:10:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-01-01Bitstream added on 2014-12-03T13:23:11Z : No. of bitstreams: 1 WOS000328699600014.pdf: 1612272 bytes, checksum: c658b8b96ccecf92446bd9f62ad0dfa8 (MD5) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background: The role of aldosterone blockers during transition from long-term compensated hypertrophy to dilated failure is not completely understood. In this study we evaluated the effects of early administration of spironolactone on cardiac remodeling, myocardial function, and mortality in spontaneously hypertensive rats (SHR). Methods: Sixteen-month-old SHR received no treatment (SHR-C, n=72) or spironolactone (SHR-SPR, 20 mg/kg/day, n=34) for six months. Echocardiogram was performed before and after treatment. Myocardial function was analyzed in left ventricular (LV) papillary muscle preparations. Myocardial collagen aund hydroxyproline concentration were evaluated by morphometry and spectrophotometry, respectively. LV gene expression was assessed by real time RT-PCR. Statistics: Student's t test; Log rank test (Kaplan Meyer). Results: SHR-C and SHR-SPR presented mortality rates of 71 and 38%, respectively (p=0.004). Systolic arterial pressure did not differ between groups (SHR-C 199 +/- 43; SHR-SPR 200 +/- 35 mmHg). Initial and final echocardiograms did not show significant differences in cardiac structures or LV function between groups. Myocardial function was similar between groups at basal and after inotropic stimulation. Collagen fractional area, hydroxyproline concentration, gene expression for alpha- and beta-myosin heavy chain, atrial natriuretic peptide, and Serca2a were not different between groups. Conclusion: Early spironolactone administration reduces mortality without changing cardiac remodeling in spontaneous hypertensive rats. Copyright (C) 2013 S. Karger AG, Basel Sao Paulo State Univ, Botucatu Med Sch, Dept Internal Med, Botucatu, SP, Brazil UNESP, Botucatu Med Sch, BR-18618970 Botucatu, SP, Brazil Univ Fed Mato Grosso do Sul, Campo Grande, Brazil Sao Paulo State Univ, Botucatu Med Sch, Dept Internal Med, Botucatu, SP, Brazil UNESP, Botucatu Med Sch, BR-18618970 Botucatu, SP, Brazil CNPq: 305013/2009-0 CNPq: 304998/2009-5 FAPESP: 07/57497-3 FAPESP: 09/54407-9 FAPESP: 09/54506-7

Made available in DSpace on 2018-12-11T17:05:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-09-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Purpose: Although increased oxidative stress is a major component of diabetic hypertensive cardiomyopathy, research into the effects of antioxidants on cardiac remodeling remains scarce. The actions of antioxidant apocynin include inhibiting reactive oxygen species (ROS) generation by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and ROS scavenging. We evaluated the effects of apocynin on cardiac remodeling in spontaneously hypertensive rats (SHR) with diabetes mellitus (DM). Methods: Male SHR were divided into four groups: control (SHR, n = 16); SHR treated with apocynin (SHR-APO; 16 mg/kg/day, added to drinking water; n = 16); diabetic SHR (SHR-DM, n = 13); and SHR-DM treated with apocynin (SHR-DM-APO, n = 14), for eight weeks. DM was induced by streptozotocin (40 mg/kg, single dose). Statistical analyzes: ANOVA and Tukey or Mann-Whitney. Results: Echocardiogram in diabetic groups showed higher left ventricular and left atrium diameters indexed for body weight, and higher isovolumetric relaxation time than normoglycemic rats; systolic function did not differ between groups. Isolated papillary muscle showed impaired contractile and relaxation function in diabetic groups. Developed tension was lower in SHR-APO than SHR. Myocardial hydroxyproline concentration was higher in SHR-DM than SHR, interstitial collagen fraction was higher in SHR-DM-APO than SHR-APO, and type III collagen protein expression was lower in SHR-DM and SHR-DM-APO than their controls. Type I collagen and lysyl oxidase expression did not differ between groups. Apocynin did not change collagen tissue. Myocardial lipid hydroperoxide concentration was higher in SHR-DM than SHR and SHR-DM-APO. Glutathione peroxidase activity was lower and catalase higher in SHR-DM than SHR. Apocynin attenuated antioxidant enzyme activity changes in SHR-DM-APO. Advanced glycation end-products and NADPH oxidase activity did not differ between groups. Conclusion: Apocynin reduces oxidative stress independently of NADPH oxidase activity and does not change ventricular or myocardial function in spontaneously hypertensive rats with diabetes mellitus. The apocynin-induced myocardial functional impairment in SHR shows that apocynin actions need to be clarified during sustained chronic pressure overload. Sao Paulo State University-UNESP Department of Internal Medicine Botucatu Medical School Sagrado Cora��o University-USC Sao Paulo State University-UNESP Department of Chemistry and Biochemistry Institute of Biosciences University of Porto Department of Physiology and Cardiothoracic Surgery Faculty of Medicine Sao Paulo University-USP Department of Cardiopneumology Medical School Sao Paulo State University-UNESP Department of Pathology Medical School Sao Paulo State University-UNESP Department of Internal Medicine Botucatu Medical School Sao Paulo State University-UNESP Department of Chemistry and Biochemistry Institute of Biosciences Sao Paulo State University-UNESP Department of Pathology Medical School FAPESP: 2015/02324-3 FAPESP: 2015/17539-5 CAPES: 306770/2015-6 CAPES: 308674/2015-4 CNPq: 308674/2015-4

Pulmonary arterial hypertension (PAH) is a chronic disease which causes overload to the right ventricle. The effect of preventive training on cardiac remodelling in this condition is still unknown. This study aimed to evaluate the influence of preventive training on hypertrophy, heart function and gene expression of calcium transport proteins in rats with monocrotaline-induced PAH. Thirty-two male Wistar rats were randomly divided into four groups: S, sedentary control; T, trained control; SM, sedentary monocrotaline; and TM, trained monocrotaline. The preventive training protocol was performed on a treadmill for 13 weeks, five times/week. The first two weeks were adopted for adaptation to training with gradual increases in speed/time. The speed of the physical training from the third to tenth weeks was gradually increased from 0.9 to 1.1 km/h for 60 min. Next, monocrotaline was applied (60 mg/kg) to induce PAH and lactate threshold analysis performed to determine the training speeds. The training speed of the TM group in the following two weeks was 0.8 km/h for 60 min and the T = 0.9 km/h for 60 min; in the final two weeks, both groups trained at the same speed and duration 0.9 km/h, 60 min. Cardiac function was assessed through echocardiography, ventricular hypertrophy through histomorphometric analysis and gene expression through RT-qPCR. Right cardiac function assessed through the peak flow velocity was SM = 75.5 cm/s vs. TM = 92.0 cm/s (P = 0.001), and ventricular hypertrophy was SM = 106.4 μm² vs. TM = 77.7 μm² (P = 0.004). There was a decrease in the gene expression of ryanodine S = 1.12 au vs. SM = 0.60 au (P = 0.02) without alterations due to training. Thus, we conclude that prior physical training exerts a cardioprotective effect on the right ventricle in the monocrotaline rat model.

Made available in DSpace on 2018-12-11T17:00:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-01-01 Objective. We evaluated the influence of exercise on functional capacity, cardiac remodeling, and skeletal muscle oxidative stress, MAPK, and NF-B pathway in rats with aortic stenosis- (AS-) induced heart failure (HF). Methods and Results. Eighteen weeks after AS induction, rats were assigned into sedentary control (C-Sed), exercised control (C-Ex), sedentary AS (AS-Sed), and exercised AS (AS-Ex) groups. Exercise was performed on treadmill for eight weeks. Statistical analyses were performed with Goodman and ANOVA or Mann-Whitney. HF features frequency and mortality did not differ between AS groups. Exercise improved functional capacity, assessed by maximal exercise test on treadmill, without changing echocardiographic parameters. Soleus cross-sectional areas did not differ between groups. Lipid hydroperoxide concentration was higher in AS-Sed than C-Sed and AS-Ex. Activity of antioxidant enzymes superoxide dismutase and glutathione peroxidase was changed in AS-Sed and restored in AS-Ex. NADPH oxidase activity and gene expression of its subunits did not differ between AS groups. Total ROS generation was lower in AS-Ex than C-Ex. Exercise modulated MAPK in AS-Ex and did not change NF-B pathway proteins. Conclusion. Exercise improves functional capacity in rats with AS-induced HF regardless of echocardiographic parameter changes. In soleus, exercise reduces oxidative stress, preserves antioxidant enzyme activity, and modulates MAPK expression. Botucatu Medical School Internal Medicine Department Sao Paulo State University (UNESP) Institute of Biosciences of Botucatu Sao Paulo State University (UNESP) Heart Institute School of Medicine University of Sao Paulo (USP) Botucatu Medical School Internal Medicine Department Sao Paulo State University (UNESP) Institute of Biosciences of Botucatu Sao Paulo State University (UNESP)