Parthenolide (PN), a major active component of the traditional herbal medicine feverfew, has been shown to have anti-inflammatory and anti-tumor properties. More remarkably, the cytotoxicity of PN seems selective to tumor cells but not their normal cell counterparts. In the present study, we investigate whether and how PN selectively enhances tumor sensitivity to radiation therapy by using prostate cancer cells LNCaP, DU145 and PC3, as well as normal prostate epithelial cells PrEC. Our study demonstrates that inhibition of NF-κB pathway and suppression of its downstream target MnSOD are common mechanisms for the radiosensitization effect of PN in prostate cancer cells. The differential susceptibility to PN in two radioresistant cancer cells, DU145 and PC3, is due, in part, to the fact that in addition to NF-κB inhibition, PN activates the PI3K/Akt pro-survival pathway in both cell lines. The presence of PTEN in DU145 cells enhances the radiosensitization effect of PN by suppression of the steady state level of activated p-Akt. We also demonstrate that PN selectively exhibits a radiosensitization effect on prostate cancer PC3 cells but not on normal prostate epithelial PrEC cells. PN causes oxidative stress in PC3 cells but not in PrEC cells, as determined by the oxidation of the ROS-sensitive probe H2DCFDA and intracellular reduced thiol and disulfide levels. In PC3 but not PrEC cells, PN activates NADPH oxidase leading to a decrease in the level of reduced thioredoxin, activation of PI3K/Akt and consequent FOXO3a phosphorylation, which results in the downregulation of FOXO3a targets, antioxidant enzyme MnSOD and catalase. Importantly, when combined with radiation, PN further increases ROS levels in PC3 cells, while it decreases radiation-induced oxidative stress in PrEC cells, possibly by increasing GSH level. Overall, our data support the concept that increasing oxidative stress in cancer cells, which are already under high constitutive oxidative stress, will lead to cell death, while the same stress may allow normal cells to maintain redox homeostasis through adaptive response. Thus, modulating cell redox status may be a novel approach to efficiently and selectively kill cancer cells.

Mecanismos redox estão envolvidos em diversos processos, como sobrevivência, proliferação e diferenciação celular, pela modulação da atividade de quinases, fosfatases e fatores de transcrição, entre outros, através da modificação oxidativa e reversível de resíduos de cisteína. Neste trabalho, nós estudamos processos redox subjacentes a diferenciação osteogênica induzida por BMP2, utilizando linhagens de células MC3T3-E1. Nosso objetivo foi investigar modificações redox como possíveis moduladores do processo de diferenciação osteogênica. Para isso, nós primeiramente caracterizamos a diferenciação osteogênica nas células MC3T3-E1 após o tratamento com BMP2, através da expressão do marcador osteogênico Osteocalcina, da fosforilação do complexo Smad 1/5/8 e da deposição de matriz extracelular calcificada. Análises de expressão gênica por qPCR mostraram que o tratamento com BMP2 resultou no aumento de expressão de NOX4, o que provavelmente leva ao aumento na produção de peróxido de hidrogênio intracelular. Nós investigamos também a modulação de peroxiredoxinas nesse processo e análises de expressão gênica mostraram que não há alterações nos níveis de expressão de Prx1 e 2 durante a diferenciação, mas os ensaios de western blot redox indicam que a Prx1 pode ser oxidada após o tratamento com BMP2, de maneira dose dependente. Outras análises in vitro mostram que células expostas a N-acetilcisteína (NAC) e PEG-catalase apresentam diferenciação osteogênica prejudicada, detectada por baixos níveis de deposição de matriz extracelular calcificada, comparado com células não-tratadas. Além disso, a fosforilação de Smad 1/5/8 são reduzidas nessas condições. Nossos dados sugerem que processos redox podem modular a sinalização celular durante o processo de diferenciação osteogência / Redox mechanisms are involved in several processes, such as cell survival, proliferation and differentiation, among other ways by modulating kinases, phosphatases and transcription factors activity that can occur through reversible and oxidative modification of cysteine residues. We were interested in studying redox processes underlying osteogenic differentiation induced by BMP-2, using MC3T3-E1 cell lineage. Our objective was to investigate redox modifications as possible modulators of the osteogenic differentiation process. We first characterized osteogenic differentiation in MC3T3-E1 cells upon BMP2 treatment, through gene expression of the osteogenic marker Osteocalcin, Smad 1/5/8 (belonging to the BMP-2 pathway) protein phosphorylation and extracellular matrix calcification. Gene expression analysis by qPCR showed that BMP2 treatment resulted in NOX4 upregulation, which probably also leads to hydrogen peroxide production. We have investigated peroxiredoxin modulation in this process, and gene expression analysis shows no significant change in peroxiredoxin 1 and 2 expression levels, but redox western blotting assays indicate that Prx1 can be oxidized after BMP2 treatment, in a dose dependent manner. In vitro analysis shows that cells exposed to N-acetyl-L-cysteine (NAC) and PEG-catalase display impaired osteogenic differentiation, detected by lower levels of calcified extracellular matrix deposition compared with non-treated cells. Moreover, phosphorylation of Smad 1/5/8 complex is reduced under these redox treatments. Our data suggest that redox pathways can modulate cell signaling during the osteogenic differentiation process

Mecanismos redox estão envolvidos em diversos processos, como sobrevivência, proliferação e diferenciação celular, pela modulação da atividade de quinases, fosfatases e fatores de transcrição, entre outros, através da modificação oxidativa e reversível de resíduos de cisteína. Neste trabalho, nós estudamos processos redox subjacentes a diferenciação osteogênica induzida por BMP2, utilizando linhagens de células MC3T3-E1. Nosso objetivo foi investigar modificações redox como possíveis moduladores do processo de diferenciação osteogênica. Para isso, nós primeiramente caracterizamos a diferenciação osteogênica nas células MC3T3-E1 após o tratamento com BMP2, através da expressão do marcador osteogênico Osteocalcina, da fosforilação do complexo Smad 1/5/8 e da deposição de matriz extracelular calcificada. Análises de expressão gênica por qPCR mostraram que o tratamento com BMP2 resultou no aumento de expressão de NOX4, o que provavelmente leva ao aumento na produção de peróxido de hidrogênio intracelular. Nós investigamos também a modulação de peroxiredoxinas nesse processo e análises de expressão gênica mostraram que não há alterações nos níveis de expressão de Prx1 e 2 durante a diferenciação, mas os ensaios de western blot redox indicam que a Prx1 pode ser oxidada após o tratamento com BMP2, de maneira dose dependente. Outras análises in vitro mostram que células expostas a N-acetilcisteína (NAC) e PEG-catalase apresentam diferenciação osteogênica prejudicada, detectada por baixos níveis de deposição de matriz extracelular calcificada, comparado com células não-tratadas. Além disso, a fosforilação de Smad 1/5/8 são reduzidas nessas condições. Nossos dados sugerem que processos redox podem modular a sinalização celular durante o processo de diferenciação osteogência / Redox mechanisms are involved in several processes, such as cell survival, proliferation and differentiation, among other ways by modulating kinases, phosphatases and transcription factors activity that can occur through reversible and oxidative modification of cysteine residues. We were interested in studying redox processes underlying osteogenic differentiation induced by BMP-2, using MC3T3-E1 cell lineage. Our objective was to investigate redox modifications as possible modulators of the osteogenic differentiation process. We first characterized osteogenic differentiation in MC3T3-E1 cells upon BMP2 treatment, through gene expression of the osteogenic marker Osteocalcin, Smad 1/5/8 (belonging to the BMP-2 pathway) protein phosphorylation and extracellular matrix calcification. Gene expression analysis by qPCR showed that BMP2 treatment resulted in NOX4 upregulation, which probably also leads to hydrogen peroxide production. We have investigated peroxiredoxin modulation in this process, and gene expression analysis shows no significant change in peroxiredoxin 1 and 2 expression levels, but redox western blotting assays indicate that Prx1 can be oxidized after BMP2 treatment, in a dose dependent manner. In vitro analysis shows that cells exposed to N-acetyl-L-cysteine (NAC) and PEG-catalase display impaired osteogenic differentiation, detected by lower levels of calcified extracellular matrix deposition compared with non-treated cells. Moreover, phosphorylation of Smad 1/5/8 complex is reduced under these redox treatments. Our data suggest that redox pathways can modulate cell signaling during the osteogenic differentiation process

A ausência de XPC, uma proteína canonicamente envolvida em reparo de DNA por excisão de nucleotídeos, está associada a vários fenótipos característicos de disfunção mitocondrial como o desequilíbrio entre os complexos da cadeia transportadora de elétrons (CTE), redução no consumo de oxigênio, maior produção de peróxido de hidrogênio, e maior sensibilidade a agentes que causam estresse mitocondrial. Contudo, uma descrição mecanística da relação entre deficiência de XPC e disfunção mitocondrial ainda não está bem estabelecida. Aqui mostramos que a deficiência de XPC está associada ao aumento na expressão do supressor de tumor p53. Essa alteração é acompanhada pelo aumento da expressão de diversas proteínas que participam em importantes funções mitocondriais. A inibição de p53 reverte a superexpressão de algumas dessas proteínas. O tratamento com o inibidor do Complexo III da CTE antimicina A induz aumento da expressão de p53 de forma mais acentuada na linhagem Xpc-/-, enquanto o tratamento com o antioxidante N-acetilcisteína diminue a produção basal de H2O2, expressão de p53 e sensibilidade aumentada ao tratamento com antimicina A. Em conjunto, nossos resultados suportam a hipótese de que o aumento da produção de H2O2 em células Xpc-/- tem um papel causal na regulação da expressão de p53 e na disfunção mitocondrial / Although XPC has been initially implicated in the nucleotide excision DNA repair pathway, its deficiency is associated with mitochondrial dysfunction, including unbalanced electron transport chain (ETC) activity, lower oxygen consumption, increased hydrogen peroxide production, and greater sensitivity to mitochondrial stress. However, a mechanistic understanding of the role of XPC in regulating mitochondrial function is still not well established. Here we show that XPC deficiency is associated with increased expression of the tumor suppressor p53, which is accompanied by increased expression of several proteins that participate in important mitochondrial functions. Inhibition of p53 reverses the overexpression of some of these proteins. In addition, treatment with the ETC inhibitor antimycin A induces p53 expression more robustly in the Xpc-/- cells, while treatment with the antioxidant N-acetylcysteine decreases basal H2O2 production, p53 expression and sensitivity to antimycin A treatment. Together, our results support a model in which increased H2O2 production in Xpc-/- causes upregulation of p53 expression and mitochondrial dysfunction

Atherosclerosis is a multifactoral inflammatory disease that occurs in predisposed locations in the vasculature where blood flow is disturbed. In vitro studies have implicated reactive oxygen species as mediators of mechanotransduction leading to inflammatory protein expression and ultimately atherogenesis. While these cell culture-based studies have provided enormous insight into the effects of WSS on endothelial biology, the applicability to the in vivo setting is questionable. We hypothesized that low magnitude oscillatory WSS acts through reactive oxygen species (ROS) to increase expression of inflammatory cell adhesion molecules leading to the development of atherosclerotic lesions. The overall objective for this thesis was to develop an in vivo flow model that produces low magnitude oscillatory WSS which could be used to investigate the in vivo molecular mechanisms of mechanotransduction. We created a novel aortic coarctation model using a shape memory nitinol clip. The clip reproducibly constricts the aorta creating a narrowing of the lumen resulting in a stenosis. This mechanical constraint produces a region of flow separation downstream from the coarctation. We have characterized the coarctation in terms of the efficacy, pressure loss, and fluid dynamics. We then measured the endothelial response of shear sensitive redox and inflammatory markers. Lastly, we utilized genetically modified mice and mice treated with pharmacological inhibitors to investigate the mechanisms involved in the expression of WSS induced inflammatory and redox markers. We found that inducing a coarctation of the aorta using a nitinol clip uniquely created a hemodynamic environment of low magnitude oscillatory WSS without a significant change in blood pressure. Using this model we found that the in vivo endothelial phenotype associated with acutely disturbed flow was characterized by increased production of superoxide and increased expression of select inflammatory proteins. In comparison, the phenotype associated with chronically disturbed flow was characterized by a more modest increase in superoxide and increased levels of multiple inflammatory proteins. We determined that in regions of acutely disturbed flow in vivo, VCAM-1 expression was not modulated by reactive oxygen species. Additionally, p47 phox-dependent NADPH Oxidase activity does not have a functional role in WSS induced superoxide generation in the endothelium. In summary, we have created a novel murine model of low magnitude oscillatory WSS that can be used to investigate the in vivo molecular mechanisms associated with atherogenesis. While previous data obtained in vitro indicated that depletion of an individual ROS was sufficient to inhibit flow-induced inflammatory protein expression, our findings, to the contrary, showed that antioxidant treatment in vivo does not inhibit shear-dependent inflammatory protein expression. Our results suggest that atherogenesis in the in vivo environment is significantly more complicated than the in vitro environment and that parallel pathways and compensatory mechanisms are likely activated in vivo in response to WSS. These results could have significant implications in the efficacy of antioxidant treatment of atherosclerosis and could explain the complexity of results observed in clinical trials.

Changes in intracellular redox homeostasis are implicated in both normal cell signaling and as pathophysiological mechanisms contributing to a variety of age-related diseases, including diabetes, atherosclerosis, neurodegenerative conditions, and cancer. Though a variety of well described mechanisms exist to counterbalance the overproduction of cellular oxidants and maintain optimal intracellular redox poise, the understanding of the mechanism(s) through which cellular redox homeostasis regulates cell signaling functions is less well understood. Here, we demonstrate that signaling by the immediate early gene / orphan nuclear hormone receptor NGFI-B (Nur77, TR3), which functions pleiotropically in the regulation of cell growth, metabolism, differentiation and death in diverse tissues, is redox-regulated at both the level of induction and NGFI-B-dependent gene transcription. Using co-immunoprecipitation experiments in cells, we also identified a novel interaction between NGFI-B and the cytoplasmic thiol-reducing catalyst thioredoxin1 (Trx1), that, similar to DTT, blocks NGFI-B-dependent gene expression in a manner that depends on the Trx1 active site cysteines. Together these observations add NGFI-B-dependent gene expression to a growing portfolio of transcription factor pathways that are redox-regulated. NGFI-B, in addition, appears to regulate the mitochondrial membrane potential in L6 skeletal myoblasts. NGFI-B is indispensible for T-cell receptor-mediated apoptosis and induces cell death in a variety of cell types in response to diverse pro-apoptotic stimuli. Like p53, translocation of NGFI-B from the nucleus to the mitochondria may be a critical aspect of its pro-apoptotic function. Interestingly, we found that enforced NGFI-B expression in L6 skeletal muscle myoblasts led to a significant decrease of MMP that peaked 48hr after transfection and did not require a cell death-inducing stimulus. Moreover, NGFI-B transfected cells had no increase in mitochondrial cytochrome C release despite loss of MMP at 48 hr. Combined, these data suggest that loss of MMP in muscle cells may be an early event in the apoptotic process regulated by NGFI-B. This, along with the redox regulation of NGFI-B, provides unique evidence of a relationship between the mitochondria, mitochondrial by-products, ROS, and the regulation of and by the transcription factor NGFI-B. / text

Fusarium graminearum causes Fusarium Head Blight, (one of) the most destructive cereal diseases in Canada. Yield loss, quality degradation and mycotoxin production make Fusarium a multifaceted threat. Regulated production of reactive oxygen species by Nox enzymes is indispensable for fungal pathogenesis. F. graminearum Nox mutant ∆noxAB produced equivalent mycotoxin but caused reduced virulence than wild-type. We hypothesized that Nox mediated redox signaling may participate in F. graminearum pathogenicity. Two-DE and gel-free biotin affinity chromatography, followed by LC-MS/MS analysis were employed for a comparative redox-proteomics analysis between wild-type and ∆noxAB to identify proteins oxidized by Nox activity. Total 35 proteins, 10 by 2-DE and 29 by gel-free system, were identified. 34% proteins participated in fungal metabolism, 20% in electron transfer reactions and 9% were anti-oxidant proteins. The findings suggested that Nox mediated thiol-disulfide exchange in proteins provide a switch for redox-dependent regulation of metabolic and developmental processes during induction of FHB.

Fusarium graminearum causes Fusarium Head Blight, (one of) the most destructive cereal diseases in Canada. Yield loss, quality degradation and mycotoxin production make Fusarium a multifaceted threat. Regulated production of reactive oxygen species by Nox enzymes is indispensable for fungal pathogenesis. F. graminearum Nox mutant ∆noxAB produced equivalent mycotoxin but caused reduced virulence than wild-type. We hypothesized that Nox mediated redox signaling may participate in F. graminearum pathogenicity. Two-DE and gel-free biotin affinity chromatography, followed by LC-MS/MS analysis were employed for a comparative redox-proteomics analysis between wild-type and ∆noxAB to identify proteins oxidized by Nox activity. Total 35 proteins, 10 by 2-DE and 29 by gel-free system, were identified. 34% proteins participated in fungal metabolism, 20% in electron transfer reactions and 9% were anti-oxidant proteins. The findings suggested that Nox mediated thiol-disulfide exchange in proteins provide a switch for redox-dependent regulation of metabolic and developmental processes during induction of FHB.

O Cor pulmonale induzido pela administração intraperitoneal de monocrotalina é um dos modelos mais utilizados para estudar os efeitos dessa síndrome sobre o sistema cardiovascular. Essa síndrome é caracterizada por um desequilíbrio no estado redox celular e uma consequente alteração no imunoconteúdo de proteínas sinalizadoras para a hipertrofia e insuficiência cardíaca. Normalmente, o peróxido de hidrogênio caracteriza-se como a espécie reativa do oxigênio mais estável, e por isso, a molécula mais envolvida com a modulação dessa sinalização. O exercício físico aeróbio tem sido extensamente estudado devido ao fato de ser uma prática que altera o estado redox celular e, consequentemente, a sinalização nos cardiomiócitos. Dessa forma, o objetivo deste estudo foi testar a hipótese de que o exercício físico poderia modular o estado redox no ventrículo direito em animais tratados com monocrotalina e, ao mesmo tempo, provocar alterações na sinalização celular, estrutura e função cardíaca. Ratos Wistar machos com aproximadamente 180 gramas de massa corporal foram treinados por quatro semanas após a injeção de monocrotalina ou solução salina. Os grupos experimentais (n=6-9 animais/grupo) foram: controle sedentário (CS) – ratos sedentários que receberam uma dose única de solução salina (i.p), monocrotalina sedentário (MS) – ratos sedentários que receberam uma dose única de monocrotalina (i.p), controle treinado (CT) - ratos treinados que receberam uma dose única de solução salina (i.p) e monocrotalina treinado (MT) - ratos treinados que receberam uma dose única de monocrotalina (i.p). As medidas hemodinâmicas foram realizadas após 24 horas da última sessão de exercício físico aeróbio. Os dados de pressão diastólica final do ventrículo direito (PDFVD), pressão sistólica do ventrículo direito (PSVD), derivada pressão/tempo máxima (dP/dtmax) e derivada pressão/tempo mínima (dP/dtmin) foram analisados. Após a análise hemodinâmica, os ratos foram mortos por deslocamento cervical e seus órgãos (coração, pulmão e fígado) foram coletados para análises morfométricas, bioquímicas e moleculares. As concentrações de peróxido de hidrogênio e a relação GSH/GSSG foram medidas obtidas com o objetivo de verificar o estado redox nos diferentes grupos experimentais. A massa dos órgãos foi utilizada para analisar a hipertrofia cardíaca, congestão pulmonar e hepática. A massa ventricular direita foi utlizada em cortes histológicos e para a análise de proteínas relacionadas com o remodelamento cardíaco pela técnica de Western Blot. A administração de monocrotalina provocou hipertrofia do ventrículo direito, congestão pulmonar, aumento da PDFVD, da PSVD, da dP/dtmax e da dP/dtmin nos animais MS e MT. Além disso, nos animais MS e CT, notamos uma redução nas concentrações de peróxido de hidrogênio, sugerindo uma modificação do sistema de defesa antioxidante provocada pela monocrotalina e pelo exercício físico. Já quanto ao volume de vasos, no grupo MS tivemos uma diminuição dessa variável em relação ao seu controle (CS), sendo que, o exercício físico preveniu este efeito nos animais MT em relação ao grupo MS. O exercício físico aeróbio promoveu uma redução no volume intersticial e na espessura da túnica média da artéria pulmonar nos animais MT. A monocrotalina provocou uma redução na relação p-GSK-3β/GSK-3β no grupo MT, sendo que que o exercício físico foi capaz de provocar um aumento nessa relação. Dessa forma, acreditamos que o exercício físico aeróbio possa alterar a função de proteínas redox-sensíveis e, dessa forma, modular a hipertrofia cardíaca nos animais que receberam a monocrotalina. / The Cor pulmonale induced by monocrotaline intraperitoneal administration is one of the most widel used models to study the effects of this syndrome on the cardiovascular system. This syndrome is characterized by an imbalance in cellular redox state and a consequent change in immunocontent of signaling proteins for hypertrophy and heart failure. Mostly, hydrogen peroxide is characterized as the most stable reactive oxygen species, and therefore the most involved molecule in the modulation of these signaling pathways. The aerobic exercise has been extensively studied due to the fact that it is a practice that alters the cellular redox state and thus signaling in cardiomyocytes. Thus, the aim of this study was to test the hypothesis that exercise could modulate the redox state of the right ventricle in animals treated with monocrotaline and, at the same time, cause changes in cell signaling, structure and cardiac function. Male Wistar rats approximately 180 grams of body mass were trained for four weeks after injection of monocrotaline or saline. The experimental groups (n = 6-9 animals / group) were: sedentary control (SC) - sedentary rats that received a single dose of saline (ip), sedentary monocrotaline (SM) - sedentary rats that received a single dose of monocrotaline (ip), trained control (TC) - trained rats that received a single dose of saline (ip) and trained monocrotaline (TM) - trained rats that received a single dose of monocrotaline (ip). Hemodynamic measurements were performed 24 hours after the last session of aerobic exercise. Data for end-diastolic pressure of the right ventricle (EDPRV), right ventricular systolic pressure (RVSP), maximum derived from pressure/time (dP/ dtmax) and minimum derived pressure/time (dP/dtmin) were analyzed. After hemodynamic analysis, mice were killed by cervical dislocation and their organs (heart, lung and liver) were colected. The hydrogen peroxide concentrations and GSH/GSSG are measurements with the aim of verifying the redox state in different experimental groups. The organ weights was used to analyze cardiac hypertrophy, pulmonary and hepatic congestion. A portion of the right ventricular mass was utilized for histological examination and other part fot analyze proteins related to cardiac remodeling, by Western blot. Morphometric analysis were performed after the removal of organs. Administration of monocrotaline caused right ventricular hypertrophy, pulmonary congestion, increased EDPRV, RVSP, dP/dtmax and dP/dtmin in SM and TM animals. Furthermore, in animals and SM and TC, we visualized a reduction in the concentrations of hydrogen peroxide, suggesting a change in the antioxidant defense system caused by monocrotaline and by exercise. Already for the volume of vessels in the SM group, we note a decrease of this variable in relation to its control (SC). At the same time, TM animals had an increase in the volume of vessels in relation to the SM group, showing that exercise promotes an increase in this item. The aerobic exercise promoted a decrease in interstitial volume and thickness of the muscle layer of the pulmonary artery in animals TM. The monocrotaline caused a decrease in the p-GSK-3β/GSK-3β in the TM group, showed that exercise was able to cause an increase in this ratio. Thus, we believe that aerobic exercise can alter the function of signaling proteins and thereby modulate cardiac hypertrophy in animals that received monocrotaline.

O Cor pulmonale induzido pela administração intraperitoneal de monocrotalina é um dos modelos mais utilizados para estudar os efeitos dessa síndrome sobre o sistema cardiovascular. Essa síndrome é caracterizada por um desequilíbrio no estado redox celular e uma consequente alteração no imunoconteúdo de proteínas sinalizadoras para a hipertrofia e insuficiência cardíaca. Normalmente, o peróxido de hidrogênio caracteriza-se como a espécie reativa do oxigênio mais estável, e por isso, a molécula mais envolvida com a modulação dessa sinalização. O exercício físico aeróbio tem sido extensamente estudado devido ao fato de ser uma prática que altera o estado redox celular e, consequentemente, a sinalização nos cardiomiócitos. Dessa forma, o objetivo deste estudo foi testar a hipótese de que o exercício físico poderia modular o estado redox no ventrículo direito em animais tratados com monocrotalina e, ao mesmo tempo, provocar alterações na sinalização celular, estrutura e função cardíaca. Ratos Wistar machos com aproximadamente 180 gramas de massa corporal foram treinados por quatro semanas após a injeção de monocrotalina ou solução salina. Os grupos experimentais (n=6-9 animais/grupo) foram: controle sedentário (CS) – ratos sedentários que receberam uma dose única de solução salina (i.p), monocrotalina sedentário (MS) – ratos sedentários que receberam uma dose única de monocrotalina (i.p), controle treinado (CT) - ratos treinados que receberam uma dose única de solução salina (i.p) e monocrotalina treinado (MT) - ratos treinados que receberam uma dose única de monocrotalina (i.p). As medidas hemodinâmicas foram realizadas após 24 horas da última sessão de exercício físico aeróbio. Os dados de pressão diastólica final do ventrículo direito (PDFVD), pressão sistólica do ventrículo direito (PSVD), derivada pressão/tempo máxima (dP/dtmax) e derivada pressão/tempo mínima (dP/dtmin) foram analisados. Após a análise hemodinâmica, os ratos foram mortos por deslocamento cervical e seus órgãos (coração, pulmão e fígado) foram coletados para análises morfométricas, bioquímicas e moleculares. As concentrações de peróxido de hidrogênio e a relação GSH/GSSG foram medidas obtidas com o objetivo de verificar o estado redox nos diferentes grupos experimentais. A massa dos órgãos foi utilizada para analisar a hipertrofia cardíaca, congestão pulmonar e hepática. A massa ventricular direita foi utlizada em cortes histológicos e para a análise de proteínas relacionadas com o remodelamento cardíaco pela técnica de Western Blot. A administração de monocrotalina provocou hipertrofia do ventrículo direito, congestão pulmonar, aumento da PDFVD, da PSVD, da dP/dtmax e da dP/dtmin nos animais MS e MT. Além disso, nos animais MS e CT, notamos uma redução nas concentrações de peróxido de hidrogênio, sugerindo uma modificação do sistema de defesa antioxidante provocada pela monocrotalina e pelo exercício físico. Já quanto ao volume de vasos, no grupo MS tivemos uma diminuição dessa variável em relação ao seu controle (CS), sendo que, o exercício físico preveniu este efeito nos animais MT em relação ao grupo MS. O exercício físico aeróbio promoveu uma redução no volume intersticial e na espessura da túnica média da artéria pulmonar nos animais MT. A monocrotalina provocou uma redução na relação p-GSK-3β/GSK-3β no grupo MT, sendo que que o exercício físico foi capaz de provocar um aumento nessa relação. Dessa forma, acreditamos que o exercício físico aeróbio possa alterar a função de proteínas redox-sensíveis e, dessa forma, modular a hipertrofia cardíaca nos animais que receberam a monocrotalina. / The Cor pulmonale induced by monocrotaline intraperitoneal administration is one of the most widel used models to study the effects of this syndrome on the cardiovascular system. This syndrome is characterized by an imbalance in cellular redox state and a consequent change in immunocontent of signaling proteins for hypertrophy and heart failure. Mostly, hydrogen peroxide is characterized as the most stable reactive oxygen species, and therefore the most involved molecule in the modulation of these signaling pathways. The aerobic exercise has been extensively studied due to the fact that it is a practice that alters the cellular redox state and thus signaling in cardiomyocytes. Thus, the aim of this study was to test the hypothesis that exercise could modulate the redox state of the right ventricle in animals treated with monocrotaline and, at the same time, cause changes in cell signaling, structure and cardiac function. Male Wistar rats approximately 180 grams of body mass were trained for four weeks after injection of monocrotaline or saline. The experimental groups (n = 6-9 animals / group) were: sedentary control (SC) - sedentary rats that received a single dose of saline (ip), sedentary monocrotaline (SM) - sedentary rats that received a single dose of monocrotaline (ip), trained control (TC) - trained rats that received a single dose of saline (ip) and trained monocrotaline (TM) - trained rats that received a single dose of monocrotaline (ip). Hemodynamic measurements were performed 24 hours after the last session of aerobic exercise. Data for end-diastolic pressure of the right ventricle (EDPRV), right ventricular systolic pressure (RVSP), maximum derived from pressure/time (dP/ dtmax) and minimum derived pressure/time (dP/dtmin) were analyzed. After hemodynamic analysis, mice were killed by cervical dislocation and their organs (heart, lung and liver) were colected. The hydrogen peroxide concentrations and GSH/GSSG are measurements with the aim of verifying the redox state in different experimental groups. The organ weights was used to analyze cardiac hypertrophy, pulmonary and hepatic congestion. A portion of the right ventricular mass was utilized for histological examination and other part fot analyze proteins related to cardiac remodeling, by Western blot. Morphometric analysis were performed after the removal of organs. Administration of monocrotaline caused right ventricular hypertrophy, pulmonary congestion, increased EDPRV, RVSP, dP/dtmax and dP/dtmin in SM and TM animals. Furthermore, in animals and SM and TC, we visualized a reduction in the concentrations of hydrogen peroxide, suggesting a change in the antioxidant defense system caused by monocrotaline and by exercise. Already for the volume of vessels in the SM group, we note a decrease of this variable in relation to its control (SC). At the same time, TM animals had an increase in the volume of vessels in relation to the SM group, showing that exercise promotes an increase in this item. The aerobic exercise promoted a decrease in interstitial volume and thickness of the muscle layer of the pulmonary artery in animals TM. The monocrotaline caused a decrease in the p-GSK-3β/GSK-3β in the TM group, showed that exercise was able to cause an increase in this ratio. Thus, we believe that aerobic exercise can alter the function of signaling proteins and thereby modulate cardiac hypertrophy in animals that received monocrotaline.