A hipertrofia cardíaca é um dos principais mecanismos de adaptação do coração frente a uma sobrecarga de trabalho e pode advir de estímulos patológicos como a hipertensão arterial levando a um prejuízo funcional ou por estímulos fisiológicos como o treinamento físico que por outro lado, promove adaptações benéficas no coração. Na última década uma nova classe de moléculas, os miRNAs, vem sendo estudada como reguladores da expressão gênica em diversos tipos celulares, inclusive os cardiomiócitos. Entretanto, estudos sobre a participação de miRNAs nas adaptações induzidas pelo treinamento físico ainda são escassos. O presente trabalho teve como principal objetivo avaliar o efeito do treinamento físico aeróbio no perfil de expressão de miRNAs no coração de ratos espontaneamente hipertensos (SHR) bem como selecionar miRNAs com padrão alterado no SHR e revertido pelo treinamento físico e analisar seu papel funcional através de aplicativos de bioinformática. Os animais foram divididos em três grupos: ratos espontaneamente hipertensos sedentários (SHR-S), SHR treinados (SHR-T) e um grupo normotenso sedentário (WKY-S). O grupo SHR-T desempenhou um protocolo de treinamento de natação de 60 minutos, 5 vezes por semana durante 10 semanas e com um sobrecarga de 5% do peso corporal na cauda. Foram feitas análises hemodinâmicas (pressão arterial, PA e freqüência cardíaca de repouso, FC), funcionais (capacidade física, consumo de oxigênio, ecocardiograma), bioquímicas a expressão de miRNAs (microarray, Real Time-PCR) e computacionais (predição de alvos e anotação de vias de sinalização). Os principais resultados foram: 1. A PA e FC reduziu no grupo SHR-T em relação aos animais sedentários; 2. A capacidade de tolerância ao esforço, VO2 pico aumentou no grupo SHR-T; 3. Análise ecocardiográfica mostrou que a onda E, Onda A e razão E/A melhoram no grupo SHR-T. 4. Análise de microarray encontrou 6 diferentes padrões no perfil de expressão de miRNAs na comparação dos grupos WKY-S, SHR-S e SHR-T; 5. 6 miRNAs alterados no SHR-S tiveram sua expressão revertida no SHR-T (miR-1, 22, 27a, 27b, 29c e 451); 7. Análise bioinformática mostrou que esse grupo de miRNAs tem como alvo predito diversas vias de sinalização relacionados com o remodelamento cardíaco como MAPK, TGF-beta e Wnt, além de vias relacionadas com estrutura do citoesqueleto e metabolismo energético. Em conclusão, nossos resultados sugerem que os miRNAs: 1, 22, 27a, 27b, 29c e 451 podem estar governando vias de sinalização celular envolvidas no processos de reversão do quadro patológico. Esse fato abre novas perspectivas a respeito da utilização dessas moléculas como forma de terapias / Cardiac hypertrophy is a major mechanism of adaptation of the heart by the increased workload and may result from pathological stimuli such as high blood pressure leading to functional impairment or by physiological stimuli such as physical training, that on other hand promotes beneficial adaptations on the heart. In the last decade a new class of molecules, miRNAs, has been studied as regulators of gene expression in different cell type, including cardiomyocytes. However, few studies have investigated the miRNAs involved in adaptations to physical training. This study aimed to evaluate the effect of aerobic exercise training on expression profiling of miRNAs in the heart of spontaneously hypertensive rats (SHR) as well as select miRNAs with altered pattern in SHR and reversed by physical training and analyze their functional role through bioinformatics applications. The animals were divided into 3 groups: sedentary hypertensive rats (SHR-S), trained SHR (SHR-T) and sedentary Wistar Kyoto rats (WKY-S). The SHR-T group performed a swimming training protocol of 60 minutes, 5 times a week for 10 weeks and with overload of 5% of body weight in the tail. We analyzed hemodynamic (blood pressure, BP and resting heart rate, HR), functional (physical capacity, oxygen consumption and echocardiogram), biochemical (microarray and Real Time-PCR to miRNAs) and computational (prediction of targets and annotation cell signaling pathways) parameters. The main findings were: 1. The BP and HR decreased in SHR-T group compared to the sedentary animals; 2. The exercise tolerance and peak VO2 increased in SHR-T group; 3.Echocardiographic analysis showed that the E wave, A wave and E/A ratio improved in SHR-T group; 4. Microarray analysis found six different miRNAs expression profile in the comparison groups WKY-S, SHR-S and SHR-T; 5. Six miRNAs were altered in SHR-S and were reversed in the SHR-T (miR-1,22, 27a, 27b, 29c and 451); 7. Bioinformatics analysis showed that this miRNA cluster has multiple predicted targets in signaling pathways related to cardiac remodeling as MAPK, Wnt and TGF-beta and others genes associate to cytoskeletal structure and energetic metabolism. In conclusion, our results suggest that miRNAs: 1, 22, 27a, 27b, 29c and 451 can be controlling cell signaling pathways involved in the process of reversing the disease. These results open new perspectives on the use of these molecules as a therapeutic treatment

Cardiac hypertrophy and heart failure (HF) remains one of the major health problems in the UK and worldwide. However, advances in their management are limited because the underlying pathological mechanisms are not completely understood. Therefore, it is important to understand novel signalling pathways leading to HF. Myocardial hypertrophy is a crucial pathophysiological process that can lead to the development of HF. Signalling initiated by members of G-protein-coupled receptors (GPCRs) proteins plays an important role in mediating cardiac hypertrophy. One member of this family, the G-protein coupled receptor 99 (GPR99), may have a crucial role in the heart because it acts as a receptor for alpha-ketoglutarate, a metabolite that is elevated in heart failure patients. GPR99 is expressed in the heart, but its precise function during cardiac pathophysiological processes is unknown. The aim of this PhD study is to investigate the role of GPR99 during cardiac hypertrophy. In this study I used in vivo and in vitro approaches to investigate whether GPR99 is directly involved in mediating cardiac hypertrophy. Mice with genetic deletion of GPR99 (GPR99-/-) exhibited a significant increase in hypertrophy following two weeks of transverse aortic constriction (TAC) as indicated by heart weight/tibia length ratio (HW/TL). In addition, GPR99-/- mice displayed increased cardiomyocytes cross-sectional area (CSA) after TAC compared to wild-type (WT) littermates. Hypertrophic markers such as brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) were also elevated in GPR99-/- mice following TAC compared to WT mice. Although interstitial fibrosis was indistinguishable in both genotypes after TAC, a precursor of fibrosis, collagen, type III, alpha1 (COL3A1) was elevated in GPR99-/- mice compared to WT mice after TAC. The baseline cardiac function as indicated by ejection fraction (EF) and fractional shortening (FS) were reduced in GPR99-/- mice compared to WT littermates following TAC. Furthermore, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), interventricular septum wall thickness (IVS) and posterior wall thickness at diastole (PW) indicated profound wall thickening and enlargement of the left ventricular (LV) chamber in GPR99-/- mice compared to WT littermates after TAC. In an attempt to examine the mechanism through which GPR99 signals during hypertrophy, I performed molecular analyses based on the data from yeast two hybrid screening showing that GPR99 interacted with COP9 signalosome element 5 (CSN5). Using immunoprecipitation assay, I found that GPR99 formed a ternary complex with CSN5 and non-receptor tyrosine kinase 2 (TYK2). TYK2 is known as a regulator of pro-hypertrophic molecules including signal transducer and activation of transcription 1 (STAT1) and STAT3. I found that the activation of these molecules was increased in GPR99-/- mice following TAC and correspondingly, adenovirus-mediated overexpression of GPR99 in neonatal rat cardiomyocytes (NRCM) blunted TYK2 phosphorylation. In conclusion, my study has identified GPR99 as a novel regulator of pathological hypertrophy via the regulation of the STAT pathway. Identification of molecules that can specifically activate or inhibit this receptor may be very useful in the development of a new therapeutic approach for cardiac hypertrophy in the future.

Cardiac hypertrophy and heart failure are affecting almost one million people in the UK alone. The available therapies of cardiac hypertrophy are for symptomatic treatment. Recently attention has been moved towards identification of novel drugs which intervene with signalling pathways involved in hypertrophy. To achieve this goal it was important to understand the role of genes involved in the development of cardiac hypertrophy. One of such genes is plasma membrane calcium ATPase isoform 4 (PMCA4). Although several studies which used genetically modified animal models suggested the involvement of PMCA4 during the development of cardiac hypertrophy, the actual role of PMCA4 is still unclear. In this study, we will clarify the role of PMCA4 during the development of cardiac hypertrophy using a novel PMCA4 specific inhibitor. Until now there is no known PMCA4 specific inhibitor so a library of 1280 medically optimised compounds was screened using a novel in vitro assay which measures the ATPase activity of PMCA4. The compound aurintricarboxylic acid (ATA) was identified, which inhibited PMCA4 ATPase activity with higher affinity (IC50= 100 nM) compared with related ATPases. In isolated neonatal rat cardiomyocytes, ATA showed dose dependent inhibition of phenylephrine-induced hypertrophy. In vivo studies showed that ATA (5mg/kg body weight/day IP) significantly reduced the development of pressure-overload induced hypertrophy in wild type mice following two weeks transverse aortic constriction (TAC). Echocardiography and haemodynamic analyses showed that ATA treatment significantly reduced the abnormal left ventricular remodelling after TAC compared with vehicle treatment. ATA treated TAC mice showed a significant reduction in the enlargement of heart weight/tibia length ratio as well as cardiomyocyte cross sectional surface area compared with vehicle treated TAC mice. A significant reduction in the expression of the hypertrophic markers ANP and BNP and, importantly, in the percentage of fibrosis was observed in ATA treated TAC mice compared with vehicle treated TAC mice. In addition, ATA treatment significantly reversed the already established pressure overload induced hypertrophy following three weeks TAC. ATA treatment to TAC mice led to a significant reduction in the expression of the bona fide calcineurin target MCIP1 and a reduction in NFAT phosphorylation level in vivo and NFAT transcriptional activity in vitro. ATA did not show a direct inhibition to the active form of calcineurin nor to the phosphatase activity of full length calcineurin.In conclusion, we have identified ATA as a novel and specific inhibitor to PMCA4 ATPase activity. Pharmacological inhibition of PMCA4 significantly reduces the hypertrophic response to pressure overload likely through inhibition of calcineurin/NFAT signalling.

Mitogen activated protein kinases (MAPK), such as ERK1/2 and p38 MAPK and phosphatidylinositol-3 phosphate kinase (PI-3K) play a major role in the development of cardiac hypertrophy. Recently, we have shown their crucial role in the regulation of the myocardial function through their effects on crucial ion channels. It is the focus of this study to resolve the interaction between these pathways and its implication on the function of the normal and hypertrophied cardiomyocytes. To that end, we created arteriovenous fistula in the adult rat that developed volume-overload eccentric cardiac hypertrophy over a 3-week period. We measured the relative activity of ERK1/2, p38 MAPKs and Akt through western blot analysis and assessed the functional density of the outward rectifier potassium current (IK) using the patch-clamp technique. The results showed a mutual negative autoregulation between ERK1/2 and p38 in normal cardiomyocytes, which disappears during cardiac hypertrophy. In addition, PI-3K seems to assume a greater role in mediating IGF-1 effects on the MAPKs during cardiac hypertrophy. This was also relevant to IK functional density which was reduced by activation of both MAPKs and Akt by angiotensin II (ANG II) and insulin-like growth factor-1 (IGF-1), respectively; however, this reduction was reversed by inhibition of PI-3K alone in hypertrophied myocytes but not in normal ones. This raises an important implication relative to the role of IGF-1-dependent activation of PI-3K, which may translate into a differential prognostic for cardiac hypertrophy among ethnic groups. This is true in African Americans, having higher circulating IGF-1 levels, and especially true for the athletes among them.

Chronic heart failure (HF) is estimated to affect 23 million people worldwide, and many patients show minimal improvement after treatment with high-potency medications. HF with reduced left ventricular ejection fraction makes up approximately half of cases and is associated with high mortality: a 5-year survival rate of only 25% after hospitalization. This disease is marked by autonomic and cardiac dysfunction, as well as increased inflammatory markers both in the brain and microbiota of the gastrointestinal tract. As a main component of the autonomic nervous system, the vagus nerve has been identified as a potential treatment target for HF. Vagus nerve stimulation (VNS) is thought to help re-balance the autonomic system and has shown promising results in clinical trials for treatment of HF. Although the mechanism of action for VNS remains partially understood, anti-inflammatory pathways have been shown to play a significant role, and these pathways may be enhanced by microbiota signaling via the vagus nerve. The goal of the current study is to provide insight into VNS treatment for HF with reduced ejection fraction via a pressure overload (PO) model. Male Sprague-Dawley rats were randomly divided into age-matched control (n=7), PO (n=6), and PO+VNS (n=11). PO rats underwent aortic constriction (~40%) to induce HF, and a subset of these had VNS leads implanted around the left cervical vagus nerve. Treatment was initiated for PO+VNS rats after reaching a 20% drop in left ventricular relative ejection fraction (EF, p<0.001). VNS was delivered using 1.0 mA pulses at 20 Hz, with 14 sec on-time followed by 66 sec off-time for 2 months to model settings used in successful clinical studies. Echocardiography to image the heart and fecal samples to assess microbiota were collected at regular intervals for all rats. Hearts were weighed at termination for a final heart to body weight ratio, and brains were processed to assess neuroinflammation. Findings indicate that while PO reduced EF ~40% at termination (p<0.05), VNS treatment restored EF back to control levels (p<0.0001 compared to study midpoint). Further, the heart/body weight ratio was increased for PO rats (p<0.05) compared to controls and PO+VNS rats. These data demonstrate that physiological markers of heart failure can be mitigated using these VNS settings. Notably, 66% of microbiota populations altered by PO were prevented with VNS treatment. Further, prolonged VNS significantly affected microbiota populations involved in inflammatory processes. Neuroinflammation was assessed in two key autonomic nuclei: paraventricular nucleus of the hypothalamus and locus coeruleus. PO displayed increased neuroinflammation as measured by microglial density in both regions, and VNS attenuated this effect (p<0.001). These findings indicate relevant contributions of inflammatory mechanisms and microbiome alterations for beneficial VNS effects leading to improved cardiac function in HF.

Pregnancy induces a dramatic change in hemodynamics due to increased blood volume and metabolic demands. The adaptation of the heart leads to physiological cardiac hypertrophy remodeling in healthy individuals during pregnancy. Metabolic syndrome (MetS) is known to predispose individuals to adverse cardiovascular event. Cardiac remodeling during pregnancy in obese individuals with or without MetS remains unclear. This study first observed differences in cardiac remodeling in human patients with excess weight during pregnancy. The pathophysiology of cardiac remodeling with pregnancy was then studied in a diet-induced animal model that recapitulates features of human MetS. Female mice fed with high fat diet (HFD) (45%kcal) for 4 months had increased body weight, impaired glucose tolerance and dyslipidemia. Pregnant female mice were kept on this HFD and were compared to nonpregnant females and normal diet (10%kcal fat) controls. HFD induced early-stage MetS led to cardiac hypertrophy at term that had features of pathological hypertrophy (PH), including fibrosis and upregulation of fetal genes associated with PH. Hearts from pregnant animals on the HFD had a distinct gene expression profile that likely underlies their pathological remodeling. Post-partum mice with preexisting MetS are also more susceptible to future pathological stimuli, with exacerbated cardiac hypertrophy and impaired cardiac function. These results suggested that preexisting MetS could change physiological into pathological cardiac remodeling during pregnancy, and predispose the heart to future cardiovascular risks. / Biomedical Sciences

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Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. The aging population and the rapidly increasing prevalence of obesity and type 2 diabetes will contribute to a growing epidemic of CVDs globally. Despite the extensive investigations in etiology, the pathogenesis of CVDs still not fully understand, and the treatment and prevention for CVDs are still limited. Significant interest has been raised in gut microbiota-host interaction since increasing evidence revealed that gut microbiomes play an important role in human health and diseases, including CVDs. Among more than two thousand gut microbiota metabolites, a compound named trimethylamine N-oxide (TMAO) was revealed to be closely related to CVDs. However, the impact of TMAO on cardiovascular health is still full of controversy and the direct impact of TMAO on heart tissue and cardiomyocytes has not been fully understood yet. In the first chapter, we reviewed the literature on TMAO-related atherosclerosis and cardiomyopathy to give us a general aspect of current research progress in the role of TMAO on CVDs. In this context, we provide an overview of the potential mechanisms underlying TMAO-induced cardiovascular diseases at the cellular and molecular levels, with a focus on atherosclerosis and cardiomyopathy. We also address the direct effects of TMAO on cardiomyocytes (a new and under-researched area) and finally propose TMAO as a potential biomarker and/or therapeutic target for the diagnosis and treatment of patients with CVDs. In the second chapter, the direct impact of TMAO on cardiac function was tested in vivo using wild-type C57B6L mice model. Four experiment groups were enrolled in the feeding protocol, which included 3w (different time points), 6w, and 13w feeding time to reveal the impact of short and longer periods of TMAO consumption on cardiac function. The plasma TMAO was measured by liquid chromatography-tandem mass spectrometry (LC/MS/MS) method at the end of the feeding protocol. Echocardiography and electrocardiography (ECG) were performed to assess the overall heart function. The histopathology staining was used to evaluate the cardiac microstructure change. By the end of the feeding protocol, the plasma TMAO all increased significantly in the TMAO group compared to the control no matter the TMAO feeding period. Echocardiography showed that 6w and 13w TMAO intake could significantly decrease cardiac contractility evidenced by decreased eject fraction (EF) and fraction shortening (FS). The electrocardiography (ECG) showed decreased R wave aptitude in 6w and 13w TMAO feed group with sinus rhythm. However, 3w TMAO intake had no impact on both cardiac contractability and ECG. Moreover, chronic TMAO supplement (13w) showed increased left ventricle (LV) mass on echocardiography and increased LV thickness on the tissue section. Further histology analysis revealed cardiomyocyte hypertrophy in the 13w TMAO-treated male group. Notably, the female mice showed significantly higher TMAO levels both in the control and treated group compared to the male, however, no gender difference was observed as to the ECG and echocardiography. In addition, the plasma inflammation cytokines were also analyzed and the tumor necrosis factor-α (TNF- α), interleukin 10 (IL-10), Fibroblast growth factor 2 (FGF β) and leptin were all increased in the 13w TMAO treated group compared to the control. These results suggest that chronic TMAO exposure led to increased plasma TMAO levels, which contribute to system inflammation and cardiac dysfunction due to cardiac hypertrophy in mice models. Research in chapter 3 demonstrates the potential underlying mechanisms of TMAO-induced cardiac dysfunction using adult mouse cardiomyocytes. In this study, we examined the direct effect of TMAO on reactive oxidative species (ROS) generation and factors related to cardiomyocyte contractibility, including, microtubule, Connexin43 (Cx43) expression, and gap junction intracellular communication (GJIC), intracellular calcium dynamics and transversal-tubule (T-tubule) both in acute and chronic TMAO challenge. Moreover, we also tested whether TMAO can enter cardiomyocytes directly. The results suggested that TMAO could enter cardiomyocytes through organic cation transporters (OCTs) and promote increased ROS generation via augmentation of NADPH oxidase 4 (Nox4). Moreover, both acute and chronic TMAO exposure could induce microtubule densification, which plays a critical role in intracellular protein transportation and cardiomyocyte morphology maintenance. We also demonstrated chronic TMAO exposure could inhibit the Cx43 expression at both cellular and tissue level, and therefore impact the GJIC for the first time. Besides, we also revealed that TMAO could interrupt intracellular calcium handling both acutely and chronically, especially documented by decreased efficiency in intracellular calcium removal, related to decreased sarcoplasmic reticulum Ca2+-ATPase (Serca2) expression. However, TMAO showed no impact on cardiomyocyte T-tubule network organization. Taken together, we demonstrated a direct destructive role of TMAO on cardiomyocytes' functional properties and provided a novel potential mechanism for TMAO-induced cardiac dysfunction. Overall, the research in this dissertation demonstrated the direct impact of TMAO on cardiomyocytes and cardiac function both in vivo and in vitro and evaluated the effect of TMAO both acutely and chronically. The TMAO can enter cardiomyocytes and induce Nox4-mediated oxidative stress, which could connect to multiple intracellular pathways, including microtubule densification, decreased Cx43 expression, and GJIC, as well as calcium handling dysfunction. Meanwhile, all these changes were closely related to the cardiomyocyte swelling observed in mice cardiac tissue after chronic TMAO consumption, which could ultimately contribute to cardiac contractile dysfunction and electrophysiology change in mice models. / Doctor of Philosophy / Cardiovascular diseases (CVDs) are a group of diseases related to our heart and blood vessels, such as heart attack and stroke. It is the leading cause of death and disability around the world, more common than diabetes and cancer. According to the reports of the American Heart Association, CVDs cost America 555 billion US dollars in 2016 while by 2035, the cost will reach 1.1 trillion. The individual, population, and economic impact of CVDs are tremendous, making CVD one of the largest public health problems at present. Despite the extensive investigations into the cause of CVDs, the exact underlying reason still not fully understand. The microbiome inside our body has raised much attention recently due to its close relationship with human health, including CVDs. The microbiome from the gut can affect our heart health both by affecting the immune system and its metabolites after we eat daily foods. Among thousands of metabolites, one named trimethylamine N-oxide (TMAO) has been shown to be related to increased CVDs risks. After we eat choline-rich food such as red meat and eggs, the gut microbiome can use these nutrients and produce TMA as metabolite waste, the TMA then goes into the liver and convert to TMAO via liver enzymes. However, the impact of TMAO on cardiovascular health is not fully understood yet. Our study uses the mice model to test whether TMAO has a direct impact on heat cells and heart function. We fed the mice with water containing 0.12% TMAO for different times including 3w, 6w, and 13w, and then check the mice's heart function through heart ultrasound and ECG. The results showed that TMAO could significantly harm heart function after long-term exposure in mice (13w). Further histology analysis of heart tissue showed increased heart cell size, which may contribute to decreased heart function. Certain blood inflammation cytokines related to CVDs also increased. The experiments using isolated mice heart cells showed that the ROS, which could harm the heart cells and related to lots of other damage processes in human health, were increased after exposure to the TMAO. Several other factors, including cell skeleton, cell channels responsible for cell-to-cell communication, and cell calcium balance were all damaged by TMAO, which could finally induce heart damage and heart diseases.

No / Catecholamines that accompany acute physiological stress are also involved in mediating the development of hypertrophy and failure. However, the cellular mechanisms involved in catecholamine-induced cardiac hypertrophy, particularly Ca2+ handling, are largely unknown. We therefore investigated the effects of cardiac hypertrophy, produced by isoprenaline, on INa/Ca and sarcoplasmic reticulum (SR) function in isolated myocytes. Methods: INa/Ca was studied in myocytes from Wistar rats, using descending (+80 to ¿110 mV) voltage ramps under steady state conditions. Myocytes were also loaded with fura-2 and either field stimulated or voltage clamped to assess [Ca2+]i and SR Ca2+ content. Results: Ca2+-dependent, steady state INa/Ca density was increased in hypertrophied myocytes (P<0.05). Ca2+ release from the SR was also increased, whereas resting [Ca2+]i and the rate of decline of [Ca2+]i to control levels were unchanged. SR Ca2+ content, estimated by using 10.0 mmol/l caffeine, was also significantly increased in hypertrophied myocytes, but only when myocytes were held and stimulated from their normal resting potential (¿80 mV) but not from ¿40 mV. However, the rate of decline of caffeine-induced Ca2+ transients or INa/Ca was not significantly different between control and hypertrophied myocytes. Ca2+-dependence of INa/Ca, examined by comparing the slope of the descending phase of the hysteresis plots of INa/Ca vs. [Ca2+]i, was also similar in the two groups of cells. Conclusion: Data show that SR Ca2+ release and SR Ca2+ content were increased in hypertrophied myocytes, despite an increase in the steady state INa/Ca density. The observation that increased SR function occurred only when myocytes were stimulated from ¿80 mV suggests that Na+ influx may play a role in altering Ca2+ homeostasis in hypertrophied cardiac muscle, possibly through increased reverse Na+/Ca2+ exchange, particularly at low stimulation frequencies.

A sobrecarga crônica de pressão causa hipertrofia, disfunção e insuficiência cardíaca (IC). O mecanismo envolvido na transição da hipertrofia cardíaca compensada para descompensada ainda não é totalmente entendido. Evidências sugerem que modificações nas proteínas contráteis poderiam contribuir para disfunção contrátil e evolução para IC. Neste sentido, estudos mostraram mudanças na expressão das proteínas da maquinaria contrátil durante o desenvolvimento da doença cardíaca como um mecanismo inicialmente benéfico. Porém, na insuficiência cardíaca, ocorrem alterações estruturais que prejudicam a contratilidade. Contudo, não se sabe ao certo quais proteínas estariam contribuindo para a transição da hipertrofia compensada para a insuficiência cardíaca. Este estudo teve como objetivo investigar as alterações das proteínas da maquinaria contrátil na transição da hipertrofia cardíaca compensada para descompensada e correlacionar essas alterações com a função cardíaca. Ratos Wistar machos foram submetidos a estenose da aorta abdominal. Após 90d da cirurgia, foram realizados ecocardiograma, análise da pressão sanguínea e os corações foram coletados para realização do Western blot e imunofluorescência para miosina de cadeia pesada, actina sarcomérica, troponina T e troponina I. Os dados foram considerados significantes quando p<0,05. Aos 90d, 70,0±5,35% dos animais apresentaram hipertrofia cardíaca (HH) e 30,3±4,79% corações hipertrofiados+dilatados (HD). A pressão arterial média aumentou 58,2% no HH e 55,0% no HD. As? expressões? de? ?-actina sarcomérica, miosina de cadeia pesada, troponina T e I aumentaram no grupo HH. No grupo HD, a miosina de cadeia pesada e a troponina T reduziram significantemente. A função sistólica manteve-se preservada nos grupos controle e HH, porém reduzida no HD. A perda estrutural da miosina de cadeia pesada e da troponina T poderia contribuir para a insuficiência cardíaca observada nesse modelo experimental. / Hypertension causes hypertrophy, cardiac dysfunction and heart failure (HF). The mechanisms implicated in the transition from compensated to decompensated cardiac hypertrophy are not fully understood. There is considerable evidence that changes in the contractile proteins may contribute to the contractile dysfunction and progression to HF. Studies have shown changes in the expression of contractile proteins during the development of heart disease as a mechanism that is initially beneficial. However, in heart failure there is an intrinsic reduction of cross-bridges that contributes to impaired contractility. It is not known which proteins are contributing to the transition from compensated hypertrophy to heart failure. We investigated ?-sarcomeric actin, heavy chain myosin and troponins T and I in the transition from compensated to decompensated cardiac hypertrophy and correlate these alterations with cardiac function. Male Wistar rats were submitted to abdominal aorta constriction and killed at 90 days post-surgery (dps). The hearts were collected; Western blot and immunofluorescence were performed to investigate ?-sarcomeric actin, heavy chain myosin and troponins T and I. Blood pressure and cardiac systolic function were evaluated. Data were considered significant when p<0.05. At 90 dps, 70,0±5,35% presented hypertrophic hearts (HH) and 30,3±4,79% hypertrophic+dilated hearts (HD). Mean blood pressure increased 58.19% in HH and 54.96% in HD. Heavy chain myosin, troponin T, troponin I and ?-sarcomeric actin expression increased in HH. In HD, only heavy chain myosin and troponin T reduced significantly. The systolic function was the same in control and HH animals and reduced in HD. The structural loss of heavy chain myosin and troponin T could contribute to heart failure observed in this experimental model of abdominal aorta constriction.