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1.
BMC Cardiovasc Disord ; 24(1): 409, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39103770

RESUMO

BACKGROUND: This study evaluated the effects of concurrent isolated training (T) or training combined with the antioxidant N-acetylcysteine (NAC) on cardiac remodeling and oxidative stress in spontaneously hypertensive rats (SHR). METHODS: Six-month-old male SHR were divided into sedentary (S, n = 12), concurrent training (T, n = 13), sedentary supplemented with NAC (SNAC, n = 13), and concurrent training with NAC supplementation (TNAC, n = 14) groups. T and TNAC rats were trained three times a week on a treadmill and ladder; NAC supplemented groups received 120 mg/kg/day NAC in rat chow for eight weeks. Myocardial antioxidant enzyme activity and lipid hydroperoxide concentration were assessed by spectrophotometry. Gene expression of NADPH oxidase subunits Nox2, Nox4, p22 phox, and p47 phox was evaluated by real time RT-PCR. Statistical analysis was performed using ANOVA and Bonferroni or Kruskal-Wallis and Dunn. RESULTS: Echocardiogram showed concentric remodeling in TNAC, characterized by increased relative wall thickness (S 0.40 ± 0.04; T 0.39 ± 0.03; SNAC 0.40 ± 0.04; TNAC 0.43 ± 0.04 *; * p < 0.05 vs T and SNAC) and diastolic posterior wall thickness (S 1.50 ± 0.12; T 1.52 ± 0.10; SNAC 1.56 ± 0.12; TNAC 1.62 ± 0.14 * mm; * p < 0.05 vs T), with improved contractile function (posterior wall shortening velocity: S 39.4 ± 5.01; T 36.4 ± 2.96; SNAC 39.7 ± 3.44; TNAC 41.6 ± 3.57 * mm/s; * p < 0.05 vs T). Myocardial lipid hydroperoxide concentration was lower in NAC treated groups (S 210 ± 48; T 182 ± 43; SNAC 159 ± 33 *; TNAC 110 ± 23 *# nmol/g tissue; * p < 0.05 vs S, # p < 0.05 vs T and SNAC). Nox 2 and p22 phox expression was higher and p47 phox lower in T than S [S 1.37 (0.66-1.66); T 0.78 (0.61-1.04) *; SNAC 1.07 (1.01-1.38); TNAC 1.06 (1.01-1.15) arbitrary units; * p < 0.05 vs S]. NADPH oxidase subunits did not differ between TNAC, SNAC, and S groups. CONCLUSION: N-acetylcysteine supplementation alone reduces oxidative stress in untreated spontaneously hypertensive rats. The combination of N-acetylcysteine and concurrent exercise further decreases oxidative stress. However, the lower oxidative stress does not translate into improved cardiac remodeling and function in untreated spontaneously hypertensive rats.


Assuntos
Acetilcisteína , Hipertensão , NADPH Oxidases , Estresse Oxidativo , Ratos Endogâmicos SHR , Remodelação Ventricular , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Hipertensão/fisiopatologia , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , NADPH Oxidases/metabolismo , NADPH Oxidases/genética , Ratos , Antioxidantes/farmacologia , Condicionamento Físico Animal , Modelos Animais de Doenças , NADPH Oxidase 2/metabolismo , NADPH Oxidase 2/genética , NADPH Oxidase 4/metabolismo , NADPH Oxidase 4/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Miocárdio/metabolismo , Miocárdio/patologia , Peróxidos Lipídicos/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Suplementos Nutricionais , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Hipertrofia Ventricular Esquerda/metabolismo
2.
Int J Mol Sci ; 25(11)2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38892020

RESUMO

Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2ß did not differ between groups (p > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats.


Assuntos
Cardiotoxicidade , Doxorrubicina , Liraglutida , Ratos Wistar , Animais , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Doxorrubicina/efeitos adversos , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Masculino , Ratos , Estresse Oxidativo/efeitos dos fármacos , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Coração/efeitos dos fármacos
3.
Int J Mol Sci ; 24(7)2023 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-37047174

RESUMO

In pathological cardiac hypertrophy, the heart is more dependent on glucose than fatty acids. This shift in energy metabolism occurs due to several factors, including the oxygen deficit, which activates hypoxia-inducible factor-1α (HIF-1α), a critical molecule related to glucose metabolism. However, there are gaps regarding the behavior of key proteins in the glycolytic pathway and HIF-1α during the transition from hypertrophy to heart failure (HF). This study assesses the hypothesis that there is an early change and enhancement of HIF-1α and the glycolytic pathway, as well as an association between them during cardiac remodeling. Sham and aortic stenosis Wistar rats were analyzed at 2, 6, and 18 weeks and in HF (n = 10-18). Cardiac structure and function were investigated by echocardiogram. Myocardial glycolysis, the aerobic and anaerobic pathways and glycogen were analyzed by enzymatic assay, Western blot, and enzyme-linked immunosorbent assay (ELISA). The following were observed: increased left ventricular hypertrophy; early diastolic function change and severe systolic and diastolic dysfunction in HF; increased HIF-1α in the 2nd week and in HF; precocious alteration and intensification of glycolysis with a shift to anaerobic metabolism from the 6th week onwards; association between HIF-1α, glycolysis, and the anaerobic pathway. Our hypothesis was confirmed as there was an early change and intensification in glucose metabolism, alteration in HIF-1α, and an association between data during the progression from hypertrophy to heart failure.


Assuntos
Insuficiência Cardíaca , Remodelação Ventricular , Ratos , Animais , Remodelação Ventricular/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ratos Wistar , Cardiomegalia , Glicólise/fisiologia , Glucose/metabolismo
4.
Med Sci Monit ; 28: e937362, 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35906764

RESUMO

Body weight has increased worldwide, characterizing a pandemic of overweight and obesity. Obesity is associated with several risk factors for cardiovascular disease. However, the association between increased body weight and cardiovascular disease is independent of the presence of classical cardiovascular disease risk factors. The direct effects of excessive fat tissue on the heart can cause a specific obesity-related cardiomyopathy in the absence of hypertension, coronary heart disease, and other structural heart diseases. Hemodynamic and structural changes contribute to obesity cardiomyopathy. The changes culminate in diastolic dysfunction, and eventually systolic dysfunction and heart failure. Several cellular cardiac changes have been described in obesity. Patients with obesity often present symptoms such as dyspnea, fatigue, lower limb edema, and chest pain. Noninvasive imaging techniques are important in assessing cardiovascular risk and evaluating symptoms. However, excess adiposity may be challenging for cardiac imaging interpretation and diagnostic accuracy. This review aims to discuss the current roles and limitations of noninvasive imaging diagnostic methods for investigating cardiovascular disease in individuals with obesity. The methods discussed include electrocardiography, echocardiography, 2-dimensional speckle tracking echocardiography, real-time 3-dimensional echocardiography, transesophageal echocardiography, computed tomography and coronary computed tomography angiography, cardiovascular magnetic resonance, stress tests ergometry, stress echocardiography, transesophageal echocardiography with pharmacological stress, stress computed tomography, stress cardiac magnetic resonance, single-photon emission computerized tomography myocardial perfusion imaging, and positron emission tomography. Although the appropriate choice of tests depends on the knowledge of methods and their limitations, patient management should be tailored according to clinical evaluation and technique availability.


Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Peso Corporal , Doenças Cardiovasculares/diagnóstico por imagem , Angiografia Coronária/métodos , Humanos , Imageamento por Ressonância Magnética , Obesidade/complicações , Obesidade/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único/métodos
5.
Heart Lung Circ ; 31(6): 894-902, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35034845

RESUMO

BACKGROUND: Mechanisms involved in cardiac remodelling by aortic regurgitation (AR) and the moment when cardiac dysfunction begins are largely unknown. This study aimed to investigate cardiac morphology and function after 1, 4, 8, and 12 weeks of experimental AR in Wistar rats. Extracellular matrix was also investigated as the potential mechanism that underlies the AR remodelling process. METHODS: Male Wistar rats underwent surgical acute AR (AR group, n=51) or a sham surgery (sham group, n=32). After the procedure, serial transthoracic echocardiograms were performed at 1, 4, 8, and 12 weeks. Morphometry of cardiac tissue and the activities of metalloproteinase 2 (MMP-2) and tissue metalloproteinase inhibitor-1 (TIMP-1) were analysed. Statistical analysis was performed by two-way ANOVA. Significance level was 5%. RESULTS: The AR group presented an increase in the sphericity index (week 1); an increase in the left atrium, left ventricular mass index, TIMP-1 and MMP-2 activities, and collagen fraction (week 4); an increase in myocyte area (week 8); and a reduction in fraction shortening (week 12). First, the chamber became more spherical; second, MMP-2 and TIMP-1 were activated and this may have contributed to hypertrophy and atrial enlargement, until systolic dysfunction occurred. CONCLUSIONS: This study showed a sequence of abnormalities that preceded myocardial dysfunction in an experimental model of AR. First, haemodynamic volume overload led to a more spherical left ventricle chamber. Second, MMP-2 and TIMP-1 transitorily increased and may have contributed to atrial enlargement, eccentric hypertrophy, and systolic dysfunction.


Assuntos
Insuficiência da Valva Aórtica , Inibidor Tecidual de Metaloproteinase-1 , Animais , Matriz Extracelular , Humanos , Hipertrofia , Masculino , Metaloproteinase 2 da Matriz , Modelos Teóricos , Ratos , Ratos Wistar , Remodelação Ventricular
6.
Heart Lung Circ ; 31(3): 365-371, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34598890

RESUMO

AIM: This study aimed to evaluate the association between serum myostatin levels, hospital mortality, and muscle mass and strength following ST-segment elevation myocardial infarction (STEMI). METHODS: This was a prospective observational study. Within 48 hours of admission, bioelectrical impedance and handgrip strength were assessed and blood samples collected for myostatin evaluation. Hospital mortality was recorded. A multiple logistic regression model was also constructed, adjusted by parameters that exhibited significant differences in the univariate analysis, to evaluate the association between myostatin levels and hospital mortality. RESULTS: One hundred and two (102) patients were included: mean age was 60.5±10.6 years, 67.6% were male, and 6.9% died during hospital stay. Univariate analysis showed that patients with lower myostatin levels had higher mortality rates. Serum myostatin levels positively correlated with handgrip strength (r=0.355; p<0.001) and appendicular skeletal muscle mass index (r=0.268; p=0.007). Receiver operating characteristic (ROC) curve analysis revealed that lower myostatin levels were associated with hospital mortality at the <2.20 ng/mL cut-off. Multiple logistic regression showed that higher serum myostatin levels were associated with reduced hospital mortality when adjusted by ß blocker use (OR, 0.228; 95% CI, 0.054-0.974; p=0.046). CONCLUSIONS: Serum myostatin concentrations positively correlated with muscle mass and strength in STEMI patients. Further assessment of serum myostatin association with mortality should be conducted using a larger sample and assessing the additive value to the Global Registry of Acute Coronary Events (GRACE) or thrombolysis in myocardial infarction (TIMI) risk scores.


Assuntos
Infarto do Miocárdio com Supradesnível do Segmento ST , Idoso , Força da Mão , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Músculos , Miostatina , Prognóstico , Medição de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico
7.
J Appl Toxicol ; 41(10): 1673-1686, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33629383

RESUMO

Dexamethasone (DEX)-induced hypertension is observed in normotensive rats, but little is known about the effects of DEX on spontaneously hypertensive animals (SHR). This study aimed to evaluate the effects of DEX on hemodynamics, cardiac hypertrophy and arterial stiffness in normotensive and hypertensive rats. Wistar rats and SHR were treated with DEX (50 µg/kg s.c., 14 d) or saline. Pulse wave velocity (PWV), echocardiographic parameters, blood pressure (BP), autonomic modulation and histological analyses of heart and thoracic aorta were performed. SHR had higher BP compared with Wistar, associated with autonomic unbalance to the heart. Echocardiographic changes in SHR (vs. Wistar) were suggestive of cardiac remodeling: higher relative wall thickness (RWT, +28%) and left ventricle mass index (LVMI, +26%) and lower left ventricle systolic diameter (LVSD, -19%) and LV diastolic diameter (LVDD, -10%), with slightly systolic dysfunction and preserved diastolic dysfunction. Also, SHR had lower myocardial capillary density and similar collagen deposition area. PWV was higher in SHR due to higher aortic collagen deposition. DEX-treated Wistar rats presented higher BP (~23%) and autonomic unbalance. DEX did not change cardiac structure in Wistar, but PWV (+21%) and aortic collagen deposition area (+21%) were higher compared with control. On the other side, DEX did not change BP or autonomic balance to the heart in SHR, but reduced RWT and LV collagen deposition area (-12% vs. SHRCT ). In conclusion, the results suggest a differential effect of dexamethasone on arterial stiffness, myocardial remodeling and blood pressure between normotensive and spontaneously hypertensive rats.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Dexametasona/toxicidade , Traumatismos Cardíacos/induzido quimicamente , Hemodinâmica/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Wistar , Rigidez Vascular/efeitos dos fármacos , Animais , Hipertensão/fisiopatologia , Ratos
8.
J Cell Mol Med ; 24(9): 5352-5362, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32239667

RESUMO

We compared the influence of aerobic and resistance exercise on cardiac remodelling, physical capacity and skeletal muscle oxidative stress in rats with MI-induced heart failure. Three months after MI induction, Wistar rats were divided into four groups: Sham; sedentary MI (S-MI); aerobic exercised MI (A-MI); and resistance exercised MI (R-MI). Exercised rats trained three times a week for 12 weeks on a treadmill or ladder. Statistical analysis was performed by ANOVA or Kruskal-Wallis test. Functional aerobic capacity was greater in A-MI and strength gain higher in R-MI. Echocardiographic parameters did not differ between infarct groups. Reactive oxygen species production, evaluated by fluorescence, was higher in S-MI than Sham, and lipid hydroperoxide concentration was lower in A-MI than the other groups. Glutathione peroxidase activity was higher in A-MI than S-MI and R-MI. Superoxide dismutase was lower in S-MI than Sham and R-MI. Gastrocnemius cross-sectional area, satellite cell activation and expression of the ubiquitin-proteasome system proteins did not differ between groups. In conclusion, aerobic exercise and resistance exercise improve functional capacity and maximum load carrying, respectively, without changing cardiac remodelling in infarcted rats. In the gastrocnemius, infarction increases oxidative stress and changes antioxidant enzyme activities. Aerobic exercise reduces oxidative stress and attenuates superoxide dismutase and glutathione peroxidase changes.


Assuntos
Coração/fisiopatologia , Músculo Esquelético/patologia , Estresse Oxidativo , Condicionamento Físico Animal , Treinamento Resistido , Remodelação Ventricular , Animais , Antioxidantes/metabolismo , Eletrocardiografia , Coração/diagnóstico por imagem , Peróxidos Lipídicos/metabolismo , Músculo Esquelético/enzimologia , Oxirredução , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Células Satélites de Músculo Esquelético/patologia
9.
J Cell Mol Med ; 24(14): 7862-7872, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32468694

RESUMO

The objective of this study was to evaluate Spondias mombin L. (SM) pulp and its influence on cardiac remodelling after myocardial infarction (MI). Male Wistar rats were assigned to four groups: a sham group (animals underwent simulated surgery) that received standard chow (S; n = 20), an infarcted group that received standard chow (MI; n = 24), an infarcted group supplemented with 100 mg of SM/kg bodyweight/d, (MIS100; n = 23) and an infarcted group supplemented with 250 mg of SM/kg bodyweight/d (MIS250; n = 22). After 3 months of treatment, morphological, functional and biochemical analyses were performed. MI induced structural and functional changes in the left ventricle with worsening systolic and diastolic function, and SM supplementation at different doses did not influence these variables as analysed by echocardiography and an isolated heart study (P > .05). However, SM supplementation attenuated cardiac remodelling after MI, reducing fibrosis (P = .047) and hypertrophy (P = .006). Biomarkers of oxidative stress, inflammatory processes and energy metabolism were further investigated in the myocardial tissue. SM supplementation improved the efficiency of energy metabolism and decreased lipid hydroperoxide in the myocardium [group S (n = 8): 267.26 ± 20.7; group MI (n = 8): 330.14 ± 47.3; group MIS100 (n = 8): 313.8 ± 46.2; group MIS250: 294.3 ± 38.0 nmol/mg tissue; P = .032], as well as decreased the activation of the inflammatory pathway after MI. In conclusion, SM supplementation attenuated cardiac remodelling processes after MI. We also found that energy metabolism, oxidative stress and inflammation are associated with this effect. In addition, SM supplementation at the highest dose is more effective.


Assuntos
Anacardiaceae/química , Suplementos Nutricionais , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Estresse Oxidativo , Extratos Vegetais/farmacologia , Remodelação Ventricular , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Biomarcadores , Peso Corporal , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Metabolismo Energético/efeitos dos fármacos , Testes de Função Cardíaca , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/etiologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Ratos , Remodelação Ventricular/efeitos dos fármacos
10.
J Cell Mol Med ; 23(9): 6504-6507, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31317657

RESUMO

We evaluated the influence of aerobic training on cardiac remodeling in untreated spontaneously hypertensive rats (SHR). Four experimental groups were used: sedentary (W-SED, n=27) and trained (WEX, n=31) normotensive Wistar rats, and sedentary (SHR-SED, n=27) and exercised (SHR-EX, n=32) hypertensive rats. At 13 months old, trained groups underwent treadmill exercise five days a week for four months. Statistical analysis: ANOVA or Kruskal-Wallis. Exercised groups had higher physical capacity. Hypertensive groups presented left ventricular (LV) concentric hypertrophy with impaired function. Left atrium diameter, LV posterior wall thickness and relative thickness, and isovolumetric relaxation time were lower in SHR-EX than SHR-SED. Interstitial collagen fraction and Type I-Type III collagen ratio were higher in SHR-SED than W-SED. In SHR-EX these parameters had intermediate values between W-EX and SHRSED with no differences between either group. Myocardial matrix metalloproteinase-2 activity, evaluated by zymography, was higher in SHR-SED than W-SED and SHR-EX. TIMP-2 was higher in hypertensive than normotensive groups. In conclusion, low intensity aerobic exercise reduces left atrium dimension and LV posterior wall thickness, and improves functional capacity, diastolic function, and metalloproteinase-2 activity in adult SHR.


Assuntos
Aorta/fisiopatologia , Hipertensão/fisiopatologia , Condicionamento Físico Animal/fisiologia , Remodelação Ventricular/fisiologia , Animais , Aorta/metabolismo , Pressão Sanguínea/fisiologia , Coração/fisiopatologia , Hipertensão/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar
11.
J Cell Mol Med ; 23(2): 1235-1245, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30456799

RESUMO

We evaluated the influence of aerobic exercise on cardiac remodelling during the transition from compensated left ventricular (LV) hypertrophy to clinical heart failure in aortic stenosis (AS) rats. Eighteen weeks after AS induction, rats were assigned into sedentary (AS) and exercised (AS-Ex) groups. Results were compared to Sham rats. Exercise was performed on treadmill for 8 weeks. Exercise improved functional capacity. Echocardiogram showed no differences between AS-Ex and AS groups. After exercise, fractional shortening and ejection fraction were lower in AS-Ex than Sham. Myocyte diameter and interstitial collagen fraction were higher in AS and AS-Ex than Sham; however, myocyte diameter was higher in AS-Ex than AS. Myocardial oxidative stress, evaluated by lipid hydroperoxide concentration, was higher in AS than Sham and was normalized by exercise. Gene expression of the NADPH oxidase subunits NOX2 and NOX4, which participate in ROS generation, did not differ between groups. Activity of the antioxidant enzyme superoxide dismutase was lower in AS and AS-Ex than Sham and glutathione peroxidase was lower in AS-Ex than Sham. Total and reduced myocardial glutathione, which is involved in cellular defence against oxidative stress, was lower in AS than Sham and total glutathione was higher in AS-Ex than AS. The MAPK JNK was higher in AS-Ex than Sham and AS groups. Phosphorylated P38 was lower in AS-Ex than AS. Despite improving functional capacity, aerobic exercise does not change LV function in AS rats. Exercise restores myocardial glutathione, reduces oxidative stress, impairs JNK signalling and further induces myocyte hypertrophy.


Assuntos
Estenose da Valva Aórtica/fisiopatologia , Glutationa Peroxidase/metabolismo , Insuficiência Cardíaca/patologia , Hipertrofia Ventricular Esquerda/patologia , Condicionamento Físico Animal , Função Ventricular Esquerda/fisiologia , Animais , Antioxidantes/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/reabilitação , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/reabilitação , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar
12.
Cell Physiol Biochem ; 50(1): 353-362, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30286450

RESUMO

BACKGROUND/AIMS: The objective of our study was to evaluate the effects of zinc supplementation on cardiac remodeling following acute myocardial infarction in rats. METHODS: Animals were subdivided into 4 groups and observed for 3 months: 1) Sham Control; 2) Sham Zinc: Sham animals receiving zinc supplementation; 3) Infarction Control; 4) Infarction Zinc. After the followup period, we studied hypertrophy and ventricular geometry, functional alterations in vivo and in vitro, changes related to collagen, oxidative stress, and inflammation, assessed by echocardiogram, isolated heart study, western blot, flow cytometer, morphometry, and spectrophotometry. RESULTS: Infarction induced a significant worsening of the functional variables. On the other hand, zinc attenuated both systolic and diastolic cardiac dysfunction induced by infarction. Considering the infarct size, there was no difference between the groups. Catalase and superoxide dismutase decreased in infarcted animals, and zinc increased its activity. We found higher expression of collagens I and III in infarcted animals, but there was no effect of zinc supplementation. Likewise, infarcted animals had higher levels of IL-10, but without zinc interference. Nrf-2 values were not different among the groups. Infarction increased the amount of Treg cells in the spleen as well as the amount of total lymphocytes. Zinc increased the amount of CD4+ in infarcted animals, but we did not observe effects in relation to Treg cells. CONCLUSION: zinc attenuates cardiac remodeling after infarction in rats; this effect is associated with modulation of antioxidant enzymes, but without the involvement of collagens I and III, Nrf-2, IL-10, and Treg cells.


Assuntos
Infarto do Miocárdio/patologia , Remodelação Ventricular/efeitos dos fármacos , Zinco/farmacologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Catalase/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Ecocardiografia , Interleucina-10/metabolismo , Masculino , Infarto do Miocárdio/veterinária , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
13.
Pathophysiology ; 25(4): 373-379, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30030016

RESUMO

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.

14.
Cell Physiol Biochem ; 44(6): 2310-2321, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29258061

RESUMO

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<0.05 AS vs Sham and AS-NAC). Malondialdehyde serum concentration was lower in AS-NAC and myocardial lipid hydroperoxide was higher in AS (Sham 199±48.1; AS 301±36.0; AS-NAC 181±41.3 nmol/g tissue). Glutathione peroxidase activity was lower in AS than Sham. Echocardiogram showed LV concentric hypertrophy with systolic and diastolic dysfunction before and after treatment; no differences were observed between AS-NAC and AS groups. NAC reduced p-ERK and p-JNK protein expression, attenuated myocardial fibrosis, and decreased the frequency of right ventricular hypertrophy. CONCLUSION: N-acetylcysteine restores myocardial total glutathione, reduces systemic and myocardial oxidative stress, improves MAPK signaling, and attenuates myocardial fibrosis in aortic stenosis rats.


Assuntos
Acetilcisteína/uso terapêutico , Antioxidantes/uso terapêutico , Estenose da Valva Aórtica/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Glutationa/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Ratos Wistar
15.
Cell Physiol Biochem ; 39(1): 371-84, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27351177

RESUMO

BACKGROUND/AIMS: Although increased oxidative stress plays a role in heart failure (HF)-induced skeletal myopathy, signaling pathways involved in muscle changes and the role of antioxidant agents have been poorly addressed. We evaluated the effects of N-acetylcysteine (NAC) on intracellular signaling pathways potentially modulated by oxidative stress in soleus muscle from HF rats. METHODS AND RESULTS: Four months after surgery, rats were assigned to Sham, myocardial infarction (MI)-C (without treatment), and MI-NAC (treated with N-acetylcysteine) groups. Two months later, echocardiogram showed left ventricular dysfunction in MI-C; NAC attenuated diastolic dysfunction. Oxidative stress was evaluated in serum and soleus muscle; malondialdehyde was higher in MI-C than Sham and did not differ between MI-C and MI-NAC. Oxidized glutathione concentration in soleus muscle was similar in Sham and MI-C, and lower in MI-NAC than MI-C (Sham 0.168 ± 0.056; MI-C 0.223 ± 0.073; MI-NAC 0.136 ± 0.023 nmol/mg tissue; p = 0.014). Western blot showed increased p-JNK and decreased p38, ERK1/2, and p-ERK1/2 in infarcted rats. NAC restored ERK1/2. NF-954;B p65 subunit was reduced; p-Ser276 in p65 and I954;B was increased; and p-Ser536 unchanged in MI-C compared to Sham. NAC did not modify NF-954;B p65 subunit, but decreased p-Ser276 and p-Ser536. CONCLUSION: N-acetylcysteine modulates MAPK and NF-954;B signaling pathways in soleus muscle of HF rats.


Assuntos
Acetilcisteína/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Esquelético/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Western Blotting , Ecocardiografia , Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Esquelético/metabolismo , Proteína MyoD/genética , Proteína MyoD/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miogenina/genética , Miogenina/metabolismo , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia
16.
Int J Exp Pathol ; 97(3): 238-47, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27365256

RESUMO

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.


Assuntos
Cardiotônicos/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Monocrotalina/farmacologia , Aerobiose , Animais , Modelos Animais de Doenças , Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/prevenção & controle , Masculino , Condicionamento Físico Animal/métodos , Ratos Wistar
17.
Am J Physiol Heart Circ Physiol ; 309(10): H1629-41, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26408546

RESUMO

Exercise training (ET) has beneficial effects on the myocardium in heart failure (HF) patients and in animal models of induced cardiac hypertrophy and failure. We hypothesized that if microRNAs (miRNAs) respond to changes following cardiac stress, then myocardial profiling of these miRNAs may reveal cardio-protective mechanisms of aerobic ET in HF. We used ascending aortic stenosis (AS) inducing HF in Wistar rats. Controls were sham-operated animals. At 18 wk after surgery, rats with cardiac dysfunction were randomized to 10 wk of aerobic ET (HF-ET) or to a heart failure sedentary group (HF-S). ET attenuated cardiac remodeling as well as clinical and pathological signs of HF with maintenance of systolic and diastolic function when compared with that of the HF-S. Global miRNA expression profiling of the cardiac tissue revealed 53 miRNAs exclusively dysregulated in animals in the HF-ET, but only 11 miRNAs were exclusively dysregulated in the HF-S. Out of 23 miRNAs that were differentially regulated in both groups, 17 miRNAs exhibited particularly high increases in expression, including miR-598, miR-429, miR-224, miR-425, and miR-221. From the initial set of deregulated miRNAs, 14 miRNAs with validated targets expressed in cardiac tissue that respond robustly to ET in HF were used to construct miRNA-mRNA regulatory networks that revealed a set of 203 miRNA-target genes involved in programmed cell death, TGF-ß signaling, cellular metabolic processes, cytokine signaling, and cell morphogenesis. Our findings reveal that ET attenuates cardiac abnormalities during HF by regulating cardiac miRNAs with a potential role in cardio-protective mechanisms through multiple effects on gene expression.


Assuntos
Remodelamento Atrial/genética , Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , MicroRNAs/genética , Condicionamento Físico Animal , Comportamento Sedentário , Remodelação Ventricular/genética , Animais , Estenose da Valva Aórtica , Apoptose , Citocinas , Modelos Animais de Doenças , Morfogênese , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
18.
Cell Physiol Biochem ; 36(4): 1453-66, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26160286

RESUMO

BACKGROUND: We evaluated the role of the aldosterone blocker spironolactone in attenuating long-term pressure overload-induced cardiac remodeling and heart failure (HF) in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: Thirteen month-old male SHR were assigned to control (SHR-C, n=20) or spironolactone (SHR-SPR, 20 mg/kg/day, n=24) groups for six months. Normotensive Wistar-Kyoto rats (WKY, n=15) were used as controls. Systolic blood pressure was higher in SHR groups and unchanged by spironolactone. Right ventricular hypertrophy, which characterizes HF in SHR, was less frequent in SHR-SPR than SHR-C. Echocardiographic parameters did not differ between SHR groups. Myocardial function was improved in SHR-SPR compared to SHR-C [developed tension: WKY 4.85±0.68; SHR-C 5.22±1.64; SHR-SPR 6.80±1.49 g/mm2; -dT/dt: WKY 18.0 (16.0­19.0); SHR-C 20.8 (18.4­25.1); SHR-SPR 28.9 (24.2­34.6) g/mm2/s]. Cardiomyocyte cross-sectional area and total collagen concentration (WKY 1.06±0.34; SHR-C 1.85±0.63; SHR-SPR 1.28±0.39 µg/mg wet tissue) were greater in SHR-C than WKY and SHR-SPR. Type 3 collagen expression was lower in SHR-C than WKY and unchanged by spironolactone. Soluble collagen, type I collagen, and lysyl oxidase did not differ between groups. CONCLUSION: Early spironolactone treatment decreases heart failure development frequency by improving myocardial systolic and diastolic function and attenuating hypertrophy and fibrosis in spontaneously hypertensive rats.


Assuntos
Insuficiência Cardíaca/prevenção & controle , Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Miocárdio/patologia , Espironolactona/uso terapêutico , Animais , Fibrose , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Hipertensão/complicações , Hipertensão/patologia , Masculino , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
19.
Cell Physiol Biochem ; 36(1): 61-74, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25924734

RESUMO

BACKGROUND: Physical exercise is a strategy to control hypertension and attenuate pressure overload-induced cardiac remodeling. The influence of exercise on cardiac remodeling during uncontrolled hypertension is not established. We evaluated the effects of a long-term low intensity aerobic exercise protocol on heart failure (HF) development and cardiac remodeling in aging spontaneously hypertensive rats (SHR). METHODS: Sixteen month old SHR (n=50) and normotensive Wistar-Kyoto (WKY, n=35) rats were divided into sedentary (SED) and exercised (EX) groups. Rats exercised in treadmill at 12 m/min, 30 min/day, 5 days/week, for four months. The frequency of HF features was evaluated at euthanasia. STATISTICAL ANALYSES: ANOVA and Tukey or Mann-Whitney, and Goodman test. RESULTS: Despite slightly higher systolic blood pressure, SHR-EX had better functional capacity and lower HF frequency than SHR-SED. Echocardiography and tissue Doppler imaging showed no differences between SHR groups. In SHR-EX, however, left ventricular (LV) systolic diameter, larger in SHR-SED than WKY-SED, and endocardial fractional shortening, lower in SHR-SED than WKY-SED, had values between those in WKY-EX and SHR-SED not differing from either group. Myocardial function, assessed in LV papillary muscles, showed improvement in SHR-EX over SHR-SED and WKY-EX. LV myocardial collagen fraction and type I and III collagen gene expression were increased in SHR groups. Myocardial hydroxyproline concentration was lower in SHR-EX than SHR-SED. Lysyl oxidase gene expression was higher in SHR-SED than WKY-SED. CONCLUSION: Exercise improves functional capacity and reduces decompensated HF in aging SHR independent of elevated arterial pressure. Improvement in functional status is combined with attenuation of LV and myocardial dysfunction and fibrosis.


Assuntos
Envelhecimento/fisiologia , Terapia por Exercício/métodos , Insuficiência Cardíaca/prevenção & controle , Hipertensão/fisiopatologia , Hipertensão/reabilitação , Animais , Modelos Animais de Doenças , Ecocardiografia Doppler , Masculino , Condicionamento Físico Animal , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
20.
Cell Physiol Biochem ; 35(1): 148-59, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25591758

RESUMO

BACKGROUND: Chronic heart failure is characterized by decreased exercise capacity with early exacerbation of fatigue and dyspnea. Intrinsic skeletal muscle abnormalities can play a role in exercise intolerance. Causal or contributing factors responsible for muscle alterations have not been completely defined. This study evaluated skeletal muscle oxidative stress and NADPH oxidase activity in rats with myocardial infarction (MI) induced heart failure. METHODS AND RESULTS: Four months after MI, rats were assigned to Sham, MI-C (without treatment), and MI-NAC (treated with N-acetylcysteine) groups. Two months later, echocardiogram showed left ventricular dysfunction in MI-C; NAC attenuated diastolic dysfunction. In soleus muscle, glutathione peroxidase and superoxide dismutase activity was decreased in MI-C and unchanged by NAC. 3-nitrotyrosine was similar in MI-C and Sham, and lower in MI-NAC than MI-C. Total reactive oxygen species (ROS) production was assessed by HPLC analysis of dihydroethidium (DHE) oxidation fluorescent products. The 2-hydroxyethidium (EOH)/DHE ratio did not differ between Sham and MI-C and was higher in MI-NAC. The ethidium/DHE ratio was higher in MI-C than Sham and unchanged by NAC. NADPH oxidase activity was similar in Sham and MI-C and lower in MI-NAC. Gene expression of p47(phox) was lower in MI-C than Sham. NAC decreased NOX4 and p22(phox) expression. CONCLUSIONS: We corroborate the case that oxidative stress is increased in skeletal muscle of heart failure rats and show for the first time that oxidative stress is not related to increased NADPH oxidase activity.


Assuntos
Acetilcisteína/farmacologia , Sequestradores de Radicais Livres/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Etídio/análogos & derivados , Etídio/análise , Glutationa Peroxidase/metabolismo , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Ventrículos do Coração/fisiopatologia , Masculino , Malondialdeído/sangue , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , NADPH Oxidase 4 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Tirosina/análogos & derivados , Tirosina/análise
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