The endocrine heart synthesises and secretes two polypeptide hormones: the natriuretic peptides (NP) atrial natriuretic factor (ANF) and B-type natriuretic peptide (BNP). The biological actions of these hormones serve both acutely and chronically to reduce systemic blood pressure and hemodynamic load to the heart, thus contributing to the maintenance of cardiorenal homeostasis. Considerable effort has been focused on the elucidation of the mechanistic underlying ANF and BNP gene expression and secretion but much remains to be determined regarding specific molecular events involved in the cardiocyte secretory function. These hormones are produced by the atrial muscle cells (cardiocytes), which display a dual secretory/muscle phenotype. In contrast, ventricular cardiocytes display mainly a muscle phenotype. Comparatively little information is available regarding the genetic background for this important phenotypic difference with particular reference to the endocrine function of the heart. We postulated that comparison of gene expression profiles between atrial and ventricular muscles would help identify transcripts that underlie the phenotypic differences associated with the endocrine function of the heart as well as identify signaling pathways involved in its regulation. The cardiac atrial and ventricular transcriptomes were analyzed using oligonucleotide microarrays under normal or chronically induced aortocaval shunt volume-overload conditions. Transcriptional differences were validated by RT-PCR and transcripts of interest were knocked-down by RNAi. Comparison of gene expression profiles in the rat heart revealed a total of 1415 differentially expressed genes between normal atrial and ventricular tissues. Functional classification and pathway analysis identified numerous transcripts involved in mechanosensing, vesicle trafficking, hormone secretion, and G protein signaling. Volume-overloaded animals exhibited a progressive increase in cardiac mass over the four-week time course, an increase in expression of known hypertrophic genes, as well as the differential expression of 700 genes within the atria. Volume-overload specifically downregulated the accessory protein for heterotrimeric G protein signaling RASD1 in the atria. In vitro, knockdown of RASD1 in the atrial-derived HL-1 cells, significantly increased ANF secretion, demonstrating a previously unknown negative modulator role for RASD1. The data developed in this investigation provides insight into the expression profiles of genes particularly centered on the secretory function of the heart under normal and chronic hemodynamic overload conditions. Genome-wide expression profile analysis identified RASD1 as being differentially expressed between cardiac tissues as well as being modulated by chronic volume overload. RASD1 emerges as a tonic inhibitor of ANF secretion. The novel function identified herein for RASD1 in the atria is of considerable interest given the fact that secretory impairment of the cardiac natriuretic hormones can negatively impact cardiovascular homeostasis.

[Truncated abstract] The innate ability of the heart to compensate for an increase in workload as a result of disease or injury, through an increase in size and mass is known as cardiac hypertrophy. The hypertrophy of the heart compensates for an increase in workload with an increase in cardiac output. However, excessive hypertrophy can result in cardiac dysfunction and substantially increases the risk of cardiac failure and mortality. The molecular mechanisms that regulate the development of cardiac hypertrophy and cardiac failure are not entirely understood. Traditionally, the G-protein Coupled Receptor (GPCR) and the downstream Mitogen-Activated Protein Kinase (MAPK) family of proteins have been implicated. However, elevated circulating and ventricular levels of several classes of cytokines also suggested that signaling by the downstream effectors of cytokine receptors, such as the Signal Transducers and Activators of Transcription (STATs), may be important. The aim of this thesis was, therefore, to characterize the involvement of MAPK and STAT pathways in regulating cardiac hypertrophy and cardiac failure. A function for MAPK and STAT signaling in regulating cardiac hypertrophy stimulated by the inflammatory cytokine IL-1Β was initially defined in primary cultures of neonatal rat cardiac myocytes. In this study, it was demonstrated that the chemical inhibition of ERK or p38MAPK was sufficient to inhibit IL-1Β-stimulated ANF expression. In contrast, simultaneous inhibition of both ERK and p38MAPK was required to ablate the hypertrophic morphology of cardiac myocytes treated with IL-1Β. These results demonstrated differential signaling from the MAPK isoforms in regulating the gene expression and morphological components of cardiac hypertrophy. In addition, it was revealed that IL-1Β treatment resulted in a delayed response (>60 min) in STAT3α tyrosine phosphorylation, which was subsequently shown to require the initial rapid activation of either ERK or p38MAPK. IL-1Β-stimulated STAT3 phosphorylation was also dependent on the de novo synthesis of secondary signaling molecules. The ablation of the STAT3 tyrosine phosphorylation by the inhibition of ERK or p38MAPK activity, correlated with the attenuation of IL-1Β-stimulated ANF expression, suggesting that signaling through STAT3α may be involved in regulating gene expression associated with IL-1Β cardiac hypertrophy

[Truncated abstract] The enlargement of the heart, also known as myocardial hypertrophy, is thought to be a compensatory process that maintains the mechanical function of the heart in response to stress factors such as pressure or volume overload. Although this process is initially compensatory, it frequently results in heart failure and death. Cardiac hypertrophy is a complex process involving changes in the individual cardiac muscle cells, cardiac myocytes. As well as the morphological changes that result from hypertrophy, there are molecular changes within each cell that regulate the hypertrophic process. These molecular changes involve many different pathways within the cardiac myocytes and remain poorly understood . . . Both STAT3α and β overexpression resulted in the upregulation of the VEGF, MnSOD and SOCS-3 genes. This indicates that in the heart, STAT3β is able to activate the gene expression of these genes in a similar manner to STAT3α. However, STAT3α or β activation alone is not enough to induce cardiac hypertrophy. In conclusion, the results presented in this thesis determined a novel role for ERK in the induction of cell death in the heart and revealed many changes in cardiac gene expression following ERK activation. These genes may be the mediators of ERK responses and their identification provides valuable information and direction for further research in this area. One consequence of ERK activation was the negative regulation of the STAT3 pathway. Further investigation revealed for the first time that the STAT3 proteins themselves may not be involved in the induction of cardiac hypertrophy and that STAT3β, initially thought to be a transcriptional repressor, can induce the expression of genes that are known to be activated by STAT3α in the heart. Therefore, these results help to better understand the roles of these two signalling pathways in the heart.

No sistema cardiovascular, os hormônios da tireoide exercem uma importante ação, influenciando a captação de cálcio, o inotropismo e o cronotropismo cardíaco e a resistência vascular periférica. No entanto, uma exacerbação destas ações, causada pelo aumento da secreção dos hormônios da tireoide, gera uma quebra desta homeostase e o desenvolvimento de hipertireoidismo. O hipertireoidismo leva ao aumento do consumo de oxigênio, gerando uma situação de estresse oxidativo. A exposição crônica ao estresse oxidativo leva à ativação de fatores de transcrição e citocinas, causando hipertrofia de cardiomiócitos e progressão para insuficiência cardíaca com inflamação e apoptose. Logo, o objetivo deste trabalho foi avaliar o papel dos hormônios da tireoide sobre a ativação de vias inflamatórias e apoptóticas mediada pelo estresse oxidativo. Neste estudo, nós avaliamos parâmetros de estresse oxidativo e algumas citocinas envolvidas com as vias de sinalização inflamatória e apoptótica. Para isso, utilizamos 60 ratos wistar, divididos em 2 grupos: Controle e Tratado (T4), com um n de 30 animais por grupo. O grupo T4 foi submetido à indução de hipertireoidismo através da adição de L-tiroxina (T4 – 12mg/L) na água de beber por 28 dias. O grupo controle não recebeu tratamento com L-tiroxina. Houve desenvolvimento de hipertireoidismo e indução de hipertrofia cardíaca no grupo T4. Verificamos também o aumento de H2O2 no coração e redução de -SH em eritrócitos no grupo T4. Houve aumento de LDH no grupo T4, indicando dano tecidual. Por fim, houve redução de PGC1-α, além de uma redução do p53 e de Bcl2 e aumento da razão Bax/Bcl2 no grupo T4. Os resultados apontam para a ocorrência de estresse oxidativo, o que com potencial dano induziu uma redução de PGC1-α e de p53, que podem estar relacionados à ativação de proteínas apoptóticas, como observado pelo aumento da razão Bax/Bcl2 no grupo tratado. / In the cardiovascular system, the thyroid hormones play an important action, influencing the uptake of calcium, the cardiac inotropy and chronotropy and peripheral vascular resistance. However, an exacerbation of these actions, caused by increased secretion of thyroid hormones, generates a breach of this homeostasis and could lead to development of hyperthyroidism. Hyperthyroidism leads to increased oxygen consumption, generating oxidative stress. Chronic exposure to oxidative stress leads to the activation of transcription factors and cytokines, causing cardiomyocyte hypertrophy and progression to heart failure with inflammation and apoptosis. Therefore, the aim of this study was to evaluate the role of thyroid hormones on the activation of inflammatory pathways and apoptotic mediated by oxidative stress. In this study, we evaluated some oxidative stress parameters and cytokines involved in inflammatory and apoptosis signaling pathways. For this, we used 60 Wistar rats, divided into 2 groups: control and treated (T4), with an n of 30 animals per group. The group T4 was subjected to hyperthyroidism induction by the addition of L-thyroxine (T4 - 12mg / L) in their drinking water for 28 days. The control group received no treatment with L-thyroxine. There was development of hyperthyroidism and induction of cardiac hypertrophy in the T4 group. We noticed the increase of H2O2 in the heart and reduced -SH in erythrocytes in the T4 group. There was LDH increase in the T4 group, indicating tissue damage. Finally, a reduction of PGC1-α, as well as a reduction of p53 and Bax/Bcl2 ratio increase in the T4 group. The results point to the occurrence of oxidative stress, which with potential damage induced a PGC1-α and p53 reduction, wich can be related to the activation of apoptotic proteins, as observed by increased Bax / Bcl2 ratio in the treated group.

Orientadora: Profa. Dra. Marcela Sorelli Carneiro Ramos / Dissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Biossistemas, 2014. / A ativação de fatores inflamatórios em um quadro de insuficiência renal isquêmica pode afetar outros órgãos, como o coração. Esses fatores lesionam o tecido cardíaco que, então, sofre um remodelamento, com a hipertrofia dos cardiomiócitos e pode evoluir para a hipertrofia cardíaca. O desenvolvimento de pesquisas com células-tronco demonstram que estas células secretam fatores que protegem o tecido cardíaco da injúria, modulam fatores inflamatórios e diminuem a formação de fibrose, o que despertou o interesse pelo seu uso em terapias para algumas cardiopatias. Este projeto teve como intuito avaliar as alterações ocasionadas pela introdução de células-tronco em modelos de hipertrofia cardíaca, devido um quadro de insuficiência renal. Para isso, camundongos C57BL/6 foram submetidos à oclusão unilateral do pedículo renal esquerdo por 60 minutos, com a aplicação de células-tronco mesenquimais via plexo retro-orbital um dia após a cirurgia. Os corações e rins dos modelos animais foram caracterizados por meio de estudos morfológicos. Os resultados obtidos demonstraram que as células-tronco preveniram o desenvolvimento da hipertrofia cardíaca, uma vez que não se verificou o aumento de massa, aumento de volume ou diminuição do lúmen do ventrículo esquerdo dos animais que receberam uma aplicação dessas células. Além disso, verificou-se também uma ação moduladora das células-tronco nos rins direitos, que não apresentaram um aumento de massa ou volume. No entanto, nenhum dado obtido demonstrou uma ação protetora dessas células nos rins esquerdos, diretamente afetados pela cirurgia de indução de lesão isquêmica. Logo, pela primeira vez, foi demonstrado que a aplicação de células-tronco mesenquimais preveniu o desenvolvimento da hipertrofia nos grupo tratados. / Activation of inflammatory factors in ischemic renal failure condition affects other organs as well as the heart. The inflammatory factors injure the cardiac tissue, modulating heart trophism with cardiomyocytes hypertrophy and this pathologic condition may progress to cardiac hypertrophy. Development of stem cell research has shown that it secrete factors that protect cardiac tissue of the injury, modulate inflammatory factors and decreases fibrosis. These discoveries have motivated studies with stem cells in cardiac diseases. This study aimed to evaluate the morphological alterations caused by the stem cells introduction on renal ischemia/reperfusion induced cardiac hypetrophy models. To analyze the stem cell effect at this model, C57BL/6 mice were subjected to unilateral occlusion of left renal pedicle for 60 minutes and one day after surgical procedures mesenchymal stem cells were applied via retro orbital sinus. Hearts and kidneys of the animal models were characterized by morphological study. and, for the first time, we evidenced that mesenchymal stem cells treatment prevents the renal ischemia/reperfusion induced cardiac hypertrophy. The results evidenced the stem cell capacity to prevent cardiac hypertrophy development, since there were no mass increase, volume increase or decrease of left ventricular lumen area on animals that received a stem cells injection. Moreover, it was verified a modulating capacity of stem cells on right kidneys that didn't presented increase in mass or volume. However, no data indicated a protective role of these cells in the left kidneys. Thus, for the first time, we evidenced that mesenchymal stem cells treatment prevents the renal ischemia/reperfusion induced cardiac hypertrophy.

Orientadora: Profa. Dra. Marcela Sorelli Carneiro Ramos / Tese (doutorado) - Universidade Federal do ABC, Programa de Pós-Graduação em Biossistemas, 2017. / A isquemia e reperfusão renal, além de causar danos nos rins, promove a instalação de quadro inflamatório sistêmico estérilatravés da liberação defatores na corrente sanguínea, que podem atingir os mais diversos órgãos, como por exemplo o coração,levando a uma série de complicações fisiológicas e morfológicas, o que caracteriza a síndrome cardiorrenal do tipo 4. A resposta iniciada por receptores do tipo Toll-like,culminana síntese de pró-IL-1?, queé clivada em IL-1?pelo inflamassoma, formado por Caspase-1, NLRP3 e ASC-1.A IL-1?se liga ao receptor IL-1R, e pode intensificar a resposta inflamatória, levando ao desenvolvimento de doenças cardiovasculares. Diante do exposto, o presente estudoobjetivou elucidar se a via de síntese ou a via ativada pelaIL-1??estaria envolvida em alterações funcionais e morfológicas no tecido cardíaco. Para tanto, camundongos machos C57BL/6J foram submetidos a isquemia e reperfusão renal (I/R),através da oclusão do pedículo renal esquerdo durante 60 minutos, seguido por reperfusão durante 8, 12 ou 15 dias. Foi administrado o antagonista comercial (Kineret)do receptor de IL-1,foram utilizadoscamundongos TLR2-/-, TLR4-/-, Casp-1-/-, NLRP3-/-, IL-1R-/-e animais tratados com clodronato (para depleção de macrófagos). A I/Rfoi capaz de induzir o desenvolvimento de hipertrofia cardíaca(HC)a partir do décimo segundo dia de reperfusão, acompanhada por alterações eletrofisiológicas (prolongamento do intervalo QT/QTc) e elevaçãonos níveis de IL-1?no soroa partir do oitavo dia de reperfusão. A ausência dos receptores TLR2 ou TLR4 foi suficiente para prevenir a HC. Interessantemente, na ausência de NLRP3ainda observou-se a HC e na ausência deCasp-1, a HC induzida foimais acentuada do que nos animais WT. Jáa interrupção da via de sinalizaçãode IL-1?foi capaz de prevenir a HC.Os resultados obtidos indicam queas vias de síntese e ativada pelaIL-1?estão envolvidasno desenvolvimento de HC em animais submetidosa I/R renal, o mesmo, no entanto não pode ser dito dos componentes NLRP3 e casp-1 do inflamassoma. Em relação as alterações eletrofisiológicas, tantoobloqueio da via de IL-1??quanto a retirada de proteínas chave na constituição do inflamossoma são capazesde prevenir alterações eletrofisiológicas provenientes da inflamação sistêmica. / Renal ischemia promotesnot only damage to the kidneys, but also a sterilesystemic inflammatorystate. Within inflammation, several inflammatory factors are released on the blood stream, reaching other organs, once they reach the heart, they can induce a stress response, leading to morphologic and physiologic changes. Such occurrence characterize type IV cardiorenal syndrome. The cardiac response may occur through activation of Toll-like receptors, resulting in synthesis of an inactive form of IL-1?and this cytokine is activated via NLRP3 inflammasome,composed by NLRP3, Caspase-1 and ASC proteins. IL-1?is activated upon assembling ofNLRP3, which may in turn intensify inflammatory response by binding to its receptor (IL-1R), leading to development of cardiovascular diseases. Therefore, the aim of thisproject was to evaluate whether IL-1?synthesis or activation pathway was involved withheart morphometric and electrophysiological alterationsinduced by I/R.Hence, we used the model of unilateral 60 minutes renal ischemia, followed by reperfusion of 8,12 or 12 days(I/R). Thus,C57bl6 male mice were treated with IL-1R commercial antagonist (Kineret), additionally, we used C57bl6TLR2-/-, TLR4-/-, Casp-1-/-, NLRP3-/-and IL-1R-/-and WT clodronate (macrophage depletion agent) treated mice. WT mice developed prolongation in QT interval after 8 days of reperfusion along with a peak of circulating IL-1?, followed by development of cardiac hypertrophy, starting at day 12. TLR2 and TLR4 absence prevented cardiac hypertrophy. Interestingly, both Kineret or clodronate treatment prevented QT prolongation, the same was observed either on knockout mice to NLRP3 inflammasome components (NLRP3 and Casp-1) or IL-1R.On the other hand, cardiac hypertrophy was more pronounced in Casp-1-/-and was not prevented on NLRP3-/-mice. Data presented here indicate that IL-1?is essential to cardiac electrophysiological alterations. Moreover, molecular pathways involved in synthesis andactivated by IL-1?participate of development of CH induced by I/R.

No sistema cardiovascular, os hormônios da tireoide exercem uma importante ação, influenciando a captação de cálcio, o inotropismo e o cronotropismo cardíaco e a resistência vascular periférica. No entanto, uma exacerbação destas ações, causada pelo aumento da secreção dos hormônios da tireoide, gera uma quebra desta homeostase e o desenvolvimento de hipertireoidismo. O hipertireoidismo leva ao aumento do consumo de oxigênio, gerando uma situação de estresse oxidativo. A exposição crônica ao estresse oxidativo leva à ativação de fatores de transcrição e citocinas, causando hipertrofia de cardiomiócitos e progressão para insuficiência cardíaca com inflamação e apoptose. Logo, o objetivo deste trabalho foi avaliar o papel dos hormônios da tireoide sobre a ativação de vias inflamatórias e apoptóticas mediada pelo estresse oxidativo. Neste estudo, nós avaliamos parâmetros de estresse oxidativo e algumas citocinas envolvidas com as vias de sinalização inflamatória e apoptótica. Para isso, utilizamos 60 ratos wistar, divididos em 2 grupos: Controle e Tratado (T4), com um n de 30 animais por grupo. O grupo T4 foi submetido à indução de hipertireoidismo através da adição de L-tiroxina (T4 – 12mg/L) na água de beber por 28 dias. O grupo controle não recebeu tratamento com L-tiroxina. Houve desenvolvimento de hipertireoidismo e indução de hipertrofia cardíaca no grupo T4. Verificamos também o aumento de H2O2 no coração e redução de -SH em eritrócitos no grupo T4. Houve aumento de LDH no grupo T4, indicando dano tecidual. Por fim, houve redução de PGC1-α, além de uma redução do p53 e de Bcl2 e aumento da razão Bax/Bcl2 no grupo T4. Os resultados apontam para a ocorrência de estresse oxidativo, o que com potencial dano induziu uma redução de PGC1-α e de p53, que podem estar relacionados à ativação de proteínas apoptóticas, como observado pelo aumento da razão Bax/Bcl2 no grupo tratado. / In the cardiovascular system, the thyroid hormones play an important action, influencing the uptake of calcium, the cardiac inotropy and chronotropy and peripheral vascular resistance. However, an exacerbation of these actions, caused by increased secretion of thyroid hormones, generates a breach of this homeostasis and could lead to development of hyperthyroidism. Hyperthyroidism leads to increased oxygen consumption, generating oxidative stress. Chronic exposure to oxidative stress leads to the activation of transcription factors and cytokines, causing cardiomyocyte hypertrophy and progression to heart failure with inflammation and apoptosis. Therefore, the aim of this study was to evaluate the role of thyroid hormones on the activation of inflammatory pathways and apoptotic mediated by oxidative stress. In this study, we evaluated some oxidative stress parameters and cytokines involved in inflammatory and apoptosis signaling pathways. For this, we used 60 Wistar rats, divided into 2 groups: control and treated (T4), with an n of 30 animals per group. The group T4 was subjected to hyperthyroidism induction by the addition of L-thyroxine (T4 - 12mg / L) in their drinking water for 28 days. The control group received no treatment with L-thyroxine. There was development of hyperthyroidism and induction of cardiac hypertrophy in the T4 group. We noticed the increase of H2O2 in the heart and reduced -SH in erythrocytes in the T4 group. There was LDH increase in the T4 group, indicating tissue damage. Finally, a reduction of PGC1-α, as well as a reduction of p53 and Bax/Bcl2 ratio increase in the T4 group. The results point to the occurrence of oxidative stress, which with potential damage induced a PGC1-α and p53 reduction, wich can be related to the activation of apoptotic proteins, as observed by increased Bax / Bcl2 ratio in the treated group.

Submitted by JÚLIO HEBER SILVA (julioheber@yahoo.com.br) on 2018-07-09T19:36:36Z No. of bitstreams: 2 Dissertação - Érika Fernandes de Jesus - 2018.pdf: 2433810 bytes, checksum: a4e4325d9ec8f6d2eac84597e2c7dfe2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-07-10T11:29:24Z (GMT) No. of bitstreams: 2 Dissertação - Érika Fernandes de Jesus - 2018.pdf: 2433810 bytes, checksum: a4e4325d9ec8f6d2eac84597e2c7dfe2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-07-10T11:29:24Z (GMT). No. of bitstreams: 2 Dissertação - Érika Fernandes de Jesus - 2018.pdf: 2433810 bytes, checksum: a4e4325d9ec8f6d2eac84597e2c7dfe2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-04-27 / Bj-PRO-7a, a proline-rich oligopeptide isolated from Bothrops jararaca snake venom, was able to reduce blood pressure and heart rate in hypertensive animals. However, it is not yet known whether this peptide may have beneficial effects on cardiac remodeling. Herein, we evaluate the effect of the Bj-PRO-7a in spontaneously hypertensive rats. Normotensive (Wistar) and spontaneously hypertensive (SHR) rats were divided into 3 groups: 1) Wistar treated with 0.9% saline, s.c.; 2) SHR treated with 0.9% saline, s.c.; and 3) SHR treated with BjPRO-7a (71 nmol/Kg/day, s.c.). The animals were treated during 28 days. The systolic blood pressure was weekly measured by tail-cuff plethysmography. At the end of the treatment, cardiac function was evaluated in isolated perfused heart preparation. The ventricular mass index was calculated by the ratio between the left ventricular weight and tibia length. The cardiomyocyte diameter and interstitial and perivascular fibrosis of the left ventricle were evaluated using the Picrossirius staining. The detection of collagen III deposition was evaluated by immunofluorescence. Fibroblast proliferation were assessed by immunohistochemistry to detect proliferating cell nuclear antigen (PCNA). The expression of catalase, SOD and ERK1/2, MMP-2 and MMP-9 was assessed by Western Blot. In our protocol, the Bj-PRO-7a was unable to reduce the systolic blood pressure of the SHRs. However, this peptide attenuated the development of the cardiomyocyte hypertrophy in these animals. Additionally, the deposition of the interstitial and perivascular fibrosis in SHR was significantly reduced by the treatment with Bj-PRO-7a. This peptide did not alter the collagen III deposition in hypertensive rat hearts. The Bj-PRO-7a reduced positive PCNA-labeled fibroblasts. The expression of catalase, SOD and ERK1/2 was significantly increased in SHR, but the Bj-PRO-7a attenuates this increase. The expression of MMP-2 and MMP-9 was not different in SHR hearts, but the Bj-PRO-7a increased the expression of the MMP-2 in the heart of these animals. Our findings demonstrate that the Bj-PRO-7a reduced the pathological cardiac remodeling through mechanism mediated by inhibition of the ERK1/2 and increasing MMP-2 expression. This data suggest that the Bj- xxiii PRO-7a could have a potential therapeutic for the treatment of cardiac diseases. / O Bj-PRO-7a é um heptapetídeo pertencente à família de oligopeptídeo rico em prolina isolado do veneno da serpente Bothrops jararaca. Estudos in vivo, mostraram que a administração aguda do heptaptídeo é capaz de reduzir a pressão arterial e a frequência cardíaca de animais hipertensos. Ainda pouco estudado e considerando os efeitos antihipertensivo e bradicardico, avaliamos o remodelamento cardíaco de animais hipertensos tratados com o Bj-PRO-7a. No presente estudo, foram utilizados ratos normotensos (Wistar) e espontaneamente hipertensos (SHR) que foram separados em 3 grupos experimentais e receberam: 1) Wistar, 0,9% NaCl, (150 µl/dia, s.c.); 2) SHR, 0,9% NaCl, (150 µl/dia, s.c.); e 3) SHR tratado com Bj-PRO-7a (71 nmol/Kg/dia, s.c.). As injeções (in bolus) foram repetidas diariamente durante 28 dias. Durante o tratamento, os animais tiveram a pressão arterial sistólica (PAS) mensurada semanalmente, pelo método não invasivo de plestimografia. No final do tratamento, a função cardíaca foi avaliada pelo método de Langendorff. A hipertrofia cardíaca de SHRs foi avaliada com análise dos seguintes parâmetros: índice de massa ventricular, diâmetro do cardiomiócito, fibrose intersticial e perivascular, colágeno III, proliferação de fibroblastos e expressão da catalase, SOD, ERK1/2, MMP-2 e MMP-9. Nossos resultados mostram que o tratamento crônico com Bj-PRO-7a não promoveu alterações importantes na PAS de SHRs. No entanto, este peptídeo atenuou o desenvolvimento da hipertrofia dos cardiomiócitos de SHRs. Apesar do Bj-PRO-7a não ter alterado a deposição de colágeno III, foi capaz de reduzir a deposição de colágeno intersticial e perivascular, bem como, a proliferação de fibroblastos em SHR. A linhagem de ratos hipertensos, tem expressão de CAT, SOD e ERK1/2 significativamente maior do que em ratos normotensos. O Bj-PRO-7a atenuou o aumento da expressão dessas enzimas / proteínas. Por outro lado, aumentou a expressão da MMP-2 ativa nos corações de ratos hipertensos. Nossos resultados mostram que o Bj-PRO-7a reduziu o remodelamento cardíaco patológico através de mecanismos mediados pela inibição da ERK1/2 e aumento da expressão da MMP-2. Dessa forma, os resultados sugerem que o Bj-PRO-7a apresenta um potencial terapêutico para desenvolvimento de fármacos para o tratamento de doenças cardiovasculares.

No sistema cardiovascular, os hormônios da tireoide exercem uma importante ação, influenciando a captação de cálcio, o inotropismo e o cronotropismo cardíaco e a resistência vascular periférica. No entanto, uma exacerbação destas ações, causada pelo aumento da secreção dos hormônios da tireoide, gera uma quebra desta homeostase e o desenvolvimento de hipertireoidismo. O hipertireoidismo leva ao aumento do consumo de oxigênio, gerando uma situação de estresse oxidativo. A exposição crônica ao estresse oxidativo leva à ativação de fatores de transcrição e citocinas, causando hipertrofia de cardiomiócitos e progressão para insuficiência cardíaca com inflamação e apoptose. Logo, o objetivo deste trabalho foi avaliar o papel dos hormônios da tireoide sobre a ativação de vias inflamatórias e apoptóticas mediada pelo estresse oxidativo. Neste estudo, nós avaliamos parâmetros de estresse oxidativo e algumas citocinas envolvidas com as vias de sinalização inflamatória e apoptótica. Para isso, utilizamos 60 ratos wistar, divididos em 2 grupos: Controle e Tratado (T4), com um n de 30 animais por grupo. O grupo T4 foi submetido à indução de hipertireoidismo através da adição de L-tiroxina (T4 – 12mg/L) na água de beber por 28 dias. O grupo controle não recebeu tratamento com L-tiroxina. Houve desenvolvimento de hipertireoidismo e indução de hipertrofia cardíaca no grupo T4. Verificamos também o aumento de H2O2 no coração e redução de -SH em eritrócitos no grupo T4. Houve aumento de LDH no grupo T4, indicando dano tecidual. Por fim, houve redução de PGC1-α, além de uma redução do p53 e de Bcl2 e aumento da razão Bax/Bcl2 no grupo T4. Os resultados apontam para a ocorrência de estresse oxidativo, o que com potencial dano induziu uma redução de PGC1-α e de p53, que podem estar relacionados à ativação de proteínas apoptóticas, como observado pelo aumento da razão Bax/Bcl2 no grupo tratado. / In the cardiovascular system, the thyroid hormones play an important action, influencing the uptake of calcium, the cardiac inotropy and chronotropy and peripheral vascular resistance. However, an exacerbation of these actions, caused by increased secretion of thyroid hormones, generates a breach of this homeostasis and could lead to development of hyperthyroidism. Hyperthyroidism leads to increased oxygen consumption, generating oxidative stress. Chronic exposure to oxidative stress leads to the activation of transcription factors and cytokines, causing cardiomyocyte hypertrophy and progression to heart failure with inflammation and apoptosis. Therefore, the aim of this study was to evaluate the role of thyroid hormones on the activation of inflammatory pathways and apoptotic mediated by oxidative stress. In this study, we evaluated some oxidative stress parameters and cytokines involved in inflammatory and apoptosis signaling pathways. For this, we used 60 Wistar rats, divided into 2 groups: control and treated (T4), with an n of 30 animals per group. The group T4 was subjected to hyperthyroidism induction by the addition of L-thyroxine (T4 - 12mg / L) in their drinking water for 28 days. The control group received no treatment with L-thyroxine. There was development of hyperthyroidism and induction of cardiac hypertrophy in the T4 group. We noticed the increase of H2O2 in the heart and reduced -SH in erythrocytes in the T4 group. There was LDH increase in the T4 group, indicating tissue damage. Finally, a reduction of PGC1-α, as well as a reduction of p53 and Bax/Bcl2 ratio increase in the T4 group. The results point to the occurrence of oxidative stress, which with potential damage induced a PGC1-α and p53 reduction, wich can be related to the activation of apoptotic proteins, as observed by increased Bax / Bcl2 ratio in the treated group.

Recentes estudos têm revelado o envolvimento de microRNAs (miRNAs) no controle da hipertrofia cardíaca e na função do miocárdio. Ainda, várias pesquisas têm demonstrado que o consumo de dieta rica em gordura pode induzir hipertrofia e remodelamento cardíaco. No presente estudo, investigou-se o efeito de dietas contendo diferentes porcentagens de gordura na expressão do miRNA-22, um miRNA que está diretamente envolvido na regulação da morfologia e da função cardíaca e um importante mediador da hipertrofia e falência cardíaca deflagradas por diferentes estímulos. Para isso, camundongos C57BL/6 machos, com idade entre 4 e 5 semanas, foram alimentados com uma dieta controle (10% das calorias provenientes de lipídeos) ou dietas hiperlipídicas (HF) contendo 45% de kcal de gordura (HF45%) e 60% de kcal de gordura (HF60%) por 10 ou 20 semanas. A dieta HF60% promoveu um aumento do peso corpóreo, aumento dos níveis de glicose, insulina, leptina, colesterol total e triglicérides e induziu intolerância a glicose. As dietas HF promoveram remodelamento cardíaco, conforme evidenciado pelo aumento no diâmetro transverso dos cardiomiócitos e deposição de colágeno. A análise de sequenciamento de RNAs demonstrou que as dietas ricas em gordura induziram padrões distintos de expressão de miRNAs no coração, incluindo o miRNA-22. Análise de bioinformática identificou a caveolina-1 como potencial alvo do miRNA-22 e seus níveis encontraram-se aumentados no grupo HF60% tratado por 20 semanas. Considerando que o miRNA-22 está envolvido no desenvolvimento da hipertrofia cardíaca e falência do coração, é possível que algumas destas alterações estruturais e funcionais cardíacas induzidas pela dieta rica em gordura sejam, ao menos em parte, influenciadas pelo aumento da expressão deste miRNA. Entretanto estudos funcionais são necessários para determinar a contribuição do miRNA-22 para os efeitos promovidos pela dieta rica em gordura no coração. / Recent studies have revealed the involvement of microRNAs (miRNAs) in the control of cardiac hypertrophy and myocardial function. In addition, several reports have demonstrated that high fat (HF) diet induces cardiac hypertrophy and remodeling. In the current study, we investigated the effect of diets containing different percentages of fat on the miRNA-22 expression, which is a miRNA involved in the control of the cardiac morphology and function and an important mediator of cardiac hypertrophy and heart failure triggered by different stimuli. To address this question, 4-week-old male C57Bl/6 mice were fed with a low fat diet (10 kcal% fat) or high fat diets (HF), containing 45 kcal% fat (HF45%) and 60 kcal% fat (HF60%) for 10 and 20 weeks. HF60% diet promoted an increase on body weight, fasting glycemia, insulin, leptin, total cholesterol, triglycerides and induced glucose intolerance. HF feeding promoted cardiac remodeling, as evidenced by increased cardiomyocyte transverse diameter and interstitial fibrosis. RNA sequencing analysis demonstrated that HF feeding induced distinct miRNA expression patterns in the heart, including miRNA-22. Bioinformatics analysis identified caveolin-1 as a potential target of miRNA-22 and its levels were increased in HF60% group treated for 20 weeks. Considering that miRNA-22 is involved in the development of cardiac hypertrophy and heart failure, it is possible that some of the cardiac structural and functional alterations induced by high fat diet are, at least in part, influenced by the increased expression of this miRNA. However functional studies are needed to determine the contribution of miRNA-22 in the effects promoted by high fat diet in the heart.