RESUMO
AIMS: Our aim was to evaluate whether the hydrogen sulfide (H2S) donor, 4-carboxyphenyl-isothiocyanate (4-CPI), exerts cardioprotective effect in the two kidney- one clip (2K-1C) rats through oxidative stress and MMP-2 activity attenuation and compare it with the classical H2S donor, Sodium Hydrosulfide (NaHS). MATERIALS AND METHODS: Renovascular hypertension (two kidneys-one clip; 2K-1C) was surgically induced in male Wistar rats. After two weeks, normotensive (2K) and hypertensive rats were intraperitoneally treated with vehicle (0.6 % dimethyl sulfoxide), NaHS (0.24 mg/Kg/day) or with 4-CPI (0.24 mg/Kg/day), for more 4 weeks. Systolic blood pressure (SBP) was evaluated weekly by tail-cuff plethysmography. Heart function was assessed by using the Millar catheter. Cardiac hypertrophy and fibrosis were evaluated by hematoxylin and eosin, and Picrosirius Red staining, respectively. The H2S was analyzed using WSP-1 fluorimetry and the cardiac oxidative stress was measured by lucigenin chemiluminescence and Amplex Red. MMP-2 activity was measured by in-gel gelatin or in situ zymography assays. Nox1, gp91phox, MMP-2 and the phospho-p65 subunit (Serine 279) nuclear factor kappa B (NF-κB) levels were evaluated by Western blotting. KEY FINDINGS: 4-CPI reduced blood pressure in hypertensive rats, decreased cardiac remodeling and promoted cardioprotection through the enhancement of cardiac H2S levels. An attenuation of oxidative stress, with inactivation of the p65-NF-κB/MMP-2 axis was similarly observed after NaHS or 4-CPI treatment in 2K-1C hypertension. SIGNIFICANCE: H2S is a mediator that promotes cardioprotective effects and decreases blood pressure, and 4-CPI seems to be a good candidate to reverse the maladaptive remodeling and cardiac dysfunction in renovascular hypertension.
Assuntos
Pressão Sanguínea , Sulfeto de Hidrogênio , Metaloproteinase 2 da Matriz , NF-kappa B , Estresse Oxidativo , Animais , Masculino , Ratos , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/farmacologia , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão Renovascular/tratamento farmacológico , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/fisiopatologia , Isotiocianatos/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Sulfetos/farmacologiaRESUMO
Studies have shown that strength training (ST) with blood flow restriction (BFR) in which low load is used (20-50% of 1 maximum voluntary contraction - MVC) can produce positive adaptations similar to ST with loads equal to or greater than 70% 1 MVC. Furthermore, recent studies have investigated the effects of STBFR on muscle adaptations, but few studies investigated the effects of STBFR on vascular function. This study aimed to evaluate the effects of the STBFR program on the vascular reactivity of the abdominal aorta of Wistar rats with femoral arteriovenous blood flow restriction. Male rats were divided into four groups: sedentary sham (S/S), sedentary with blood flow restriction (S/BFR), trained sham (T/S), and trained with blood flow restriction (T/BFR). The animals in the S/BFR and T/BFR groups underwent surgery to BFR in the femoral artery and vein. After one week, the trained groups started the ST which consisted of climbing ladder, six sets of 10 repetitions with 50% of 1 MVC assessed by maximum loaded weight (MLW) carried out for four weeks. Concentration-response curves to Acetylcholine (ACh: 10 nM - 100 µM) and Phenylephrine (PHE: 1 nM - 30 µM) were performed in aortic rings with intact endothelium. The production of nitric oxide (NO) and reactive oxygen species (ROS) in situ and the vascular remodeling marker (MMP-2) were also measured. The ST increased the strength of the T/S and T/BFR groups in MLW tests. The S/BFR group showed a 22% reduction in relaxation to acetylcholine, but exercise prevented this reduction in the T/BFR group. In animals without BFR, ST did not alter the response to acetylcholine. An increase in NO production was seen in T/S and T/BFR showed a reduction in ROS production (62% and 40%, respectively). In conclusion low load ST with BFR promotes similar vascular function responses to ST without BFR. Low load ST with and without BFR is interventions that can improve performance with similar magnitudes. Both training methods could have some benefits for vascular health due to NO production in the aorta increased in the T/S group and decreased production of reactive oxygen species in the T/BFR group.
Assuntos
Adaptação Fisiológica , Aorta/fisiologia , Óxido Nítrico/metabolismo , Condicionamento Físico Animal , Espécies Reativas de Oxigênio/metabolismo , Fluxo Sanguíneo Regional , Treinamento Resistido , Animais , Hemodinâmica , Masculino , Força Muscular , Músculo Esquelético/fisiologia , Ratos , Ratos WistarRESUMO
PURPOSE: Cardiac transition from concentric (C-LVH) to eccentric left ventricle hypertrophy (E-LVH) is a maladaptive response of hypertension. Matrix metalloproteinases (MMPs), in particular MMP-2, may contribute to tissue remodeling by proteolyzing extra- and intracellular proteins. Troponin I and dystrophin are two potential targets of MMP-2 examined in this study and their proteolysis would impair cardiac contractile function. We hypothesized that MMP-2 contributes to the decrease in troponin I and dystrophin in the hypertensive heart and thereby controls the transition from C-LVH to E-LVH and cardiac dysfunction. METHODS: Male Wistar rats were divided into sham or two kidney-1 clip (2K-1C) hypertensive groups and treated with water (vehicle) or doxycycline (MMP inhibitor, 15 mg/kg/day) by gavage from the tenth to the sixteenth week post-surgery. Tail-cuff plethysmography, echocardiography, gelatin zymography, confocal microscopy, western blot, mass spectrometry, in silico protein analysis and immunofluorescence were performed. RESULTS: 6 out of 23 2K-1C rats (26%) had E-LVH followed by reduced ejection fraction. The remaining had C-LVH with preserved cardiac function. Doxycycline prevented the transition from C-LVH to E-LVH. MMP activity is increased in C-LVH and E-LVH hearts which was inhibited by doxycycline. This effect was associated with an increase in troponin I cleavage products and a decline in dystrophin in the left ventricle of E-LVH rats, which was prevented by doxycycline. CONCLUSION: Hypertension causes increased cardiac MMP-2 activity which proteolyzes troponin I and dystrophin, contributing to the transition from C-LVH to E-LVH and cardiac dysfunction.
Assuntos
Doxiciclina/farmacologia , Distrofina/metabolismo , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Metaloproteinase 2 da Matriz/metabolismo , Troponina I/metabolismo , Animais , Antibacterianos/farmacologia , Distrofina/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Metaloproteinase 2 da Matriz/genética , Inibidores de Metaloproteinases de Matriz/farmacologia , Ratos , Ratos Wistar , Troponina I/genéticaRESUMO
Even though the coronary reperfusion process is the most important tool to preserve cardiac function, after myocardial infarction, reperfusion of acutely ischemic myocardium can induce injury. We aimed to evaluate the functional and molecular aspects 4 weeks after myocardial ischemia-reperfusion (IR) in rats. Male Wistar rats (N = 47) were subjected to myocardial IR by short-term (30 min) ligation and subsequent reperfusion of the left descending coronary artery. Control rats (N = 7) underwent the same surgical maneuver without coronary ligation. After 4 weeks, rats had their cardiac function examined by ventricular pressure recording under basal condition or pharmacological stress. Myocardial fibrosis and molecular mediators of IR injury (reactive oxygen species, tumor necrosis factor-alpha and matrix-metalloproteinase-2) were assessed as well. Most of the rats subjected to IR did not show macroscopic signs of infarct, while only 17% of these animals showed large myocardial infarction scars. Of note, all animals submitted to IR presented the functional and molecular parameters altered when compared with the control subjects. Cardiac function was attenuated in all animals submitted to IR, regardless the presence or size of macroscopic cardiac scars. Interstitial fibrosis, matrix-metalloproteinase-2 activity and the expression of tumor necrosis factor-alpha were higher in the myocardium of all IR rats as compared to the control subjects (p<0.05). Myocardium superoxide anion and hydrogen peroxide were increased in rats without or with mild cardiac scars. These results show that IR leads to myocardial injury in rats. Besides, even the animals with an apparent healthy myocardium (without infarct scar) presented cardiac dysfunction and molecular changes that may contribute to the development of heart failure over time.
Assuntos
Cicatriz/patologia , Cicatriz/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Animais , Cicatriz/metabolismo , Colágeno/metabolismo , Modelos Animais de Doenças , Coração/fisiopatologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Pressão VentricularRESUMO
Selenium (Se) is an essential trace element involved in several biological pathways, naturally found in rocks, soils, and food. Even though the daily requirement of Se is achieved through a balanced diet, the use of Se supplements has been frequent. Due to the risk of toxic effects of having Se in excess, supplementation is still under debate. The aim was to evaluate the effects of long-term Se supplementation upon systolic blood pressure (SBP) and redox status of rats exposed to sodium selenite. Male Wistar rats were exposed to 2 and 6 mg/L of sodium selenite in drinking water for 85 days. SBP and body weight were evaluated weekly; oxidative stress biomarkers were measured in blood or plasma; and Se levels were assessed in blood, plasma, kidney, and liver. Se supplementation (2 and 6 mg/L) induced significant increase in the SBP in rats from the 42nd day until the end of the study. This increase on SBP was not associated with significant changes in oxidative stress biomarkers. A significant increase in Se levels was found in whole blood, kidney, and liver from both groups of rats receiving Se supplementation when compared to control. Although the exact mechanisms underlying this augment in SBP are not clear, they are potentially related to other Se biological routes besides the synthesis of selenoproteins, such as GSH-Px. Due to the negative effects upon blood pressure, precautionary measures are advised, since the selling of supplements does not require a medical prescription.
Assuntos
Peso Corporal/fisiologia , Suplementos Nutricionais , Hipertensão/fisiopatologia , Selenito de Sódio/administração & dosagem , Animais , Peso Corporal/efeitos dos fármacos , Catalase/sangue , Catalase/metabolismo , Glutationa/sangue , Glutationa/metabolismo , Glutationa Peroxidase/sangue , Glutationa Peroxidase/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Rim/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/sangue , Malondialdeído/metabolismo , Distribuição Aleatória , Ratos Wistar , Selênio/sangue , Selênio/metabolismo , Selenito de Sódio/efeitos adversos , Fatores de TempoRESUMO
BACKGROUND: Several evidences report that a vegetarian diet is protector against cardiovascular diseases. Few studies have demonstrated the circulating profile of cardiovascular biomarkers in vegetarians. Therefore, the aims of the current study were compared the plasma concentrations of myeloperoxidase (MPO), metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 between healthy vegetarian (Veg) and healthy omnivorous (Omn). METHODS: Using ELISA and multiplexed bead immunoassay, we measured in plasma from 43 Veg and 41 Omn the cardiovascular biomarkers concentrations cited above. RESULTS: We found significant lower concentrations of MPO, MMP-9, MMP-2 and MMP-9/TIMP-1 ratio in Veg compared to Omn (all P<0.05). Moreover, MMP-9 concentrations were correlated positively with leukocytes and neutrophils count in both groups (all P<0.05). CONCLUSION: A vegetarian diet is associated with a healthier profile of cardiovascular biomarkers compared to omnivorous.
Assuntos
Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Voluntários Saudáveis , Vegetarianos , Dieta , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoensaio , MasculinoRESUMO
For vascular remodeling in hypertension, it is essential that vascular smooth muscle cells (VSMCs) reshape in order to proliferate and migrate. The extracellular matrix (ECM) needs to be degraded to favor VSMC migration. Many proteases, including matrix metalloproteinases (MMPs), contribute to ECM proteolysis and VSMC migration. Bioactive peptides, hemodynamic forces and reactive oxygen-nitrogen species regulate MMP-2 expression and activity. Increased MMP-2 activity contributes to hypertension-induced maladaptive arterial changes and sustained hypertension. New ECM is synthesized to supply VSMCs with bioactive mediators, which stimulate hypertrophy. MMP-2 stimulates the interaction of VSMCs with newly formed ECM, which triggers intracellular signaling via integrins to induce a phenotypic switch and persistent migration. VSMCs switch from a contractile to a synthetic phenotype in order to migrate and contribute to vascular remodeling in hypertension. MMPs also disrupt growth factors bound to ECM, thus contributing to their capacity to regulate VSMC migration. This review sheds light on the proteolytic effects of MMP-2 on ECM and non-ECM substrates in the vasculature and how these effects contribute to VSMC migration in hypertension. The inhibition of MMP activity as a therapeutic target may make it possible to reduce arterial maladaptation caused by hypertension and prevent the resulting fatal cardiovascular events.