Myocardial dysfunction is an important manifestation of sepsis/septic shock. Activation of Phosphatidylinositol 3-kinase(PI3K)/protein kinase B (Akt) signaling pathway has been shown to improve cardiac performance during sepsis/septic shock. We have reported previously that α-lipoic acid (LA) activates PI3K/Akt pathway in neuronal cells. It is possible, therefore, that treatment with LA will attenuate cardiac dysfunction during sepsis/septic shock through a PI3K/Akt-dependent mechanism. To test this possibility, we treated mice with LA prior to lipopolysaccharide (LPS) challenge. Cardiac function was analyzed by echocardiography 6 h after LPS challenge. LPS significantly suppressed cardiac function as evidenced by decreases in EF% and FS% in mice. However, LA pretreatment significantly attenuated cardiac dysfunction following LPS challenge. LA pretreatment also improved survival in LPS-challenged mice. Furthermore, LA markedly attenuated the LPS-induced inflammatory response in myocardium, as evidenced by decreases in the upregulation of VCAM-1, ICAM-1 and iNOS, as well as myocardial leucocytes infiltration. Moreover, LPS challenge significantly decreased the phosphorylation levels of Akt and Gsk-3β, which was prevented by LA pretreatment. More importantly, inhibition of PI3K/Akt signaling by Wortmannin (WM) completely abrogated the LA-induced protection in cardiac dysfunction following LPS challenge. Collectively, our results demonstrated that LA improved cardiac function during endotoxemia. The mechanism was through, at least in part, preserved activation of the PI3K/Akt signaling.

Aims Inadequate healing after myocardial infarction (MI) leads to heart failure and fatal ventricular rupture, while optimal healing requires timely induction and resolution of inflammation. This study tested the hypothesis that heat shock protein B1 (HSPB1), which limits myocardial inflammation during endotoxemia, modulates wound healing after MI. Methods and results To test this hypothesis, cardiomyocyte-specific HSPB1 knockout (Hspb1-/-) mice were generated using the Cre-LoxP recombination system. MI was induced by ligation of the left anterior descending coronary artery in Hspb1-/- and wild-type (WT) littermates. HSPB1 was up-regulated in cardiomyocytes of WT animals in response to MI, and deficiency of cardiomyocyte HSPB1 increased MI-induced cardiac rupture and mortality within 21 days after MI. Serial echocardiography showed more aggravated remodelling and cardiac dysfunction in Hspb1-/- mice than in WT mice at 1, 3, and 7 days after MI. Decreased collagen deposition and angiogenesis, as well as increased MMP2 and MMP9 activity, were also observed in Hspb1-/- mice compared with WT controls after MI, using immunofluorescence, polarized light microscopy, and zymographic analyses. Notably, Hspb1-/- hearts exhibited enhanced and prolonged leucocyte infiltration, enhanced expression of inflammatory cytokines, and enhanced TLR4/MyD88/NFκB activation compared with WT controls after MI. In-depth molecular analyses in both mice and primary cardiomyocytes demonstrated that cardiomyocyte-specific knockout of HSPB1 increased nuclear factor-κB (NFκB) activation, which promoted the expression of proinflammatory mediators. This led to increased leucocyte recruitment, thereby to excessive inflammation, ultimately resulting in adverse remodelling, cardiac dysfunction, and cardiac rupture following MI. Conclusion These data suggest that HSPB1 acts as a negative regulator of NFκB-mediated leucocyte recruitment and the subsequent inflammation in cardiomyocytes. Cardiomyocyte HSPB1 is required for wound healing after MI and could be a target for myocardial repair in MI patients.

Cardiovascular dysfunction is a major complication associated with sepsis induced mortality. Cardiac fibrosis plays a critical role in sepsis induced cardiac dysfunction. The mechanisms of the activation of cardiac fibrosis is unclarified. In this study, we found that microRNA-23b (miR-23b) was up-regulated in heart tissue during cecal ligation and puncture (CLP)-induced sepsis and transfection of miR-23b inhibitor improved survival in late sepsis. Inhibition of miR-23b in the myocardium protected against cardiac output and enhanced left ventricular systolic function. miR-23b inhibitor also alleviated cardiac fibrosis in late sepsis. MiR-23b mediates the activation of TGF-β1/Smad2/3 signaling to promote the differentiation of cardiac fibroblasts through suppression of 5′TG3′-interacting factor 1 (TGIF1). MiR-23b also induces AKT/N-Cadherin signaling to contribute to the deposition of extracellular matrix by inhibiting phosphatase and tensin homologue (PTEN). TGIF1 and PTEN were confirmed as the targets of miR-23b in vitro by Dual-Glo Luciferase assay. miR-23b inhibitor blocked the activation of adhesive molecules and restored the imbalance of pro-fibrotic and anti-fibrotic factors. These data provide direct evidence that miR-23b is a critical contributor to the activation of cardiac fibrosis to mediate the development of myocardial dysfunction in late sepsis. Blockade of miR-23b expression may be an effective approach for prevention sepsis-induced cardiac dysfunction.

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The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly reached pandemic proportions, and knowledge about this virus and coronavirus disease 2019 (COVID-19) has expanded rapidly. This review focuses primarily on mechanisms that contribute to acute cardiac injury and dysfunction, which are common in patients with severe disease. The etiology of cardiac injury is multifactorial, and the extent is likely enhanced by pre-existing cardiovascular disease. Disruption of homeostatic mechanisms secondary to pulmonary pathology ranks high on the list, and there is growing evidence that direct infection of cardiac cells can occur. Angiotensin converting enzyme 2 (ACE2) plays a central role in COVID-19 and is a necessary receptor for viral entry into human cells. ACE2 normally not only eliminates angiotensin II (Ang II) by converting it to Ang (1-7), but also elicits a beneficial response profile counteracting that of Ang II. Molecular analyses of single nuclei from human hearts have shown that ACE2 is most highly expressed by pericytes. Given the important roles that pericytes have in the microvasculature, infection of these cells could compromise myocardial supply to meet metabolic demand. Furthermore, ACE2 activity is crucial for opposing adverse effects of locally generated Ang II, so virus-mediated internalization of ACE2 could exacerbate pathology by this mechanism. While the role of cardiac pericytes in acute heart injury by SARS-CoV-2 requires investigation, expression of ACE2 by these cells has broader implications for cardiac pathophysiology.

Cardiac dysfunction accelerates the risk of heart failure, and its pathogenesis involves a complex interaction between genetic and environmental factors. Variations in myosin affect contractile abilities of cardiomyocytes and cause structural and functional abnormalities in myocardium. The study aims to find the association of MYH7 rs121913642 (c.1594 T>C) and rs121913645 (c.667G>A) variants with cardiac dysfunction in the Punjabi Pakistani population. Patients with heart failure (n = 232) and healthy controls (n = 205) were enrolled in this study. MYH7 variant genotyping was performed using tetra ARMS-PCR. MYH7 rs121913642 TC genotype was significantly more prevalent in the patient group (p < 0.001). However, MYH7 rs121913645 genotype frequencies were not significantly different between the patient and control groups (p < 0.666). Regression analysis also revealed that the rs121913642 C allele increases the risk of cardiac failure by ~2 [OR:1.98, CI: 1.31–2.98, p < 0.001] in comparison to the T allele. High levels of the cardiac enzymes cardiac troponin I (cTnI) and CK-MB were observed in patients. There was also an increase in total cholesterol, LDL cholesterol, and uric acid in patients compared to the healthy control group (p < 0.001). In conclusion, the MYH7 gene variant rs121913642 is genetically associated with cardiac dysfunction and involved in the pathogenesis of HF.

O infarto do miocárdio é atualmente considerado a etiologia que mais contribui para o aparecimento de insuficiência cardíaca (IC) em humanos. Em detrimento a hiperativação de fatores neuro-humorais, a progressão da IC é caracterizada por uma série de anormalidades celulares associadas à disfunção ventricular. Dentre estas anormalidades, alterações na função e dinâmica mitocondrial merecem destaque, uma vez que a homeostase da organela é essencial para a viabilidade celular e o bom funcionamento da bomba cardíaca. No presente estudo, caracterizamos em modelo animal de disfunção cardíaca associada ao infarto do miocárdio: a) fenótipo cardíaco; b) função mitocondrial; c) equilíbrio redox; e d) dinâmica mitocondrial. Nossos resultados nos permitem afirmar que doze semanas após a cirurgia de infarto do miocárdio, os animais desenvolveram importantes alterações fenotípicas como aumento da massa cardíaca, dilatação ventricular, hipertrofia do cardiomiócito e maior deposição de tecido fibroso cardíaco, que contribuíram para o estabelecimento da disfunção ventricular. Além disso, foi possível confirmar a instalação do quadro de disfunção mitocondrial cardíaca, representada pela redução na capacidade respiratória e perda da homeostase redox. Por fim, encontramos um aumento no número de mitocôndrias cardíacas com menor diâmetro, alterações que vieram acompanhadas de uma menor atividade das enzimas relacionadas à fusão mitocondrial. Uma vez caracterizada a função e a dinâmica mitocondrial na disfunção cardíaca, avaliamos o efeito do treinamento físico aeróbico (TF) nessas variáveis. O TF, atualmente utilizado como um adjuvante no tratamento das doenças cardiovasculares, foi eficaz em promover o remodelamento cardíaco reverso e melhorar a função cardíaca nos animais infartados. Além disso, melhorou a capacidade respiratória e reduziu o estresse oxidativo, restaurando a função mitocondrial. Aliado a esses achados, o TF normalizou a atividade das enzimas relacionadas à dinâmica mitocondrial, fato associado à normalização do número e tamanho da organela. Esses resultados demonstram que a disfunção cardíaca induzida por infarto do miocárdio está associada à um quadro de mitocondriopatia em ratos, com alterações tanto na função quanto estrutura mitocondrial, e que o TF desencadeia efeitos benéficos na manutenção da integridade/função mitocondrial e melhora da função contrátil cardíaca / Myocardial infarction is considered the etiology that most contributes to the onset of heart failure in humans. Among the ventricular dysfunction-associated cellular abnormalities, changes in mitochondrial function and dynamics are critical, since the organelle homeostasis is crucial in maintaining the metabolic, electrical and mechanical properties of the heart. In the present study, we characterized in cardiac dysfunction- induced myocardial infarction in rats: a) cardiac phenotype; b) mitochondrial metabolism; c) redox balance, and d) mitochondrial dynamics. Our results show that twelve weeks after myocardial surgery, the animals developed pathological cardiac remodeling-associated ventricular dysfunction. Furthermore, we observed a reduced mitochondrial respiratory capacity and loss of redox homeostasis. Finally, we found a lower activity of enzymes related to mitochondrial fusion, these changes were accompanied by an increase in the number of small mitochondria. Once characterized mitochondrial function and dynamics, we evaluated the effect of exercise training in these variables in rats with cardiac dysfunction. The exercise training, currently established as an important non-pharmacological treatment for cardiovascular diseases, reversed the pathological cardiac remodeling and minimized the ventricular dysfunction in infarcted animals. Furthermore, exercise training restored the mitochondrial function by increasing respiratory capacity and reducing oxidative stress. Finally, exercise training restored the activity of mitochondrial dynamics-related enzymes and morphology. Taken together, our findings uncover the potential benefits of exercise training in reversing the cardiac mitochondriopathy observed in failing hearts, reinforcing the importance of this intervention as a non-pharmacological tool for heart failure therapy

Orientador: Bertha Furlan Polegato / Resumo: Introdução: A doxorrubicina é um quimioterápico amplamente utilizado e muito eficaz no tratamento de neoplasias, porém pode levar à cardiotoxicidade, o que pode limitar seu uso. Os mecanismos envolvidos no surgimento da cardiotoxicidade são múltiplos, mas o aumento do estresse oxidativo tem papel fundamental. O suco de laranja contém muitos compostos com potencial antioxidante, como os flavonóides. A composição do suco de laranja pode diferir entre as variedades de laranja e isso pode levar a efeitos biológicos diferentes, como maior atividade antioxidante. Objetivo: Avaliar a influência do suco de laranja Pera (Citrus sinensis) e da Moro (Citrus sinensis (L.) Osbeck) na cardiotoxicidade induzida pela doxorrubicina em ratos. Material e Métodos: Foram utilizados 120 ratos Wistar machos adultos, que foram alocados em 6 grupos: C, LP, LM, D, DLP, DLM. Os grupos C e D receberam água com maltodextrina para igualar a quantidade de carboidratos dos sucos de laranja. Os grupos LP e DLP receberam suco de laranja Pera e os grupos LM e DLM receberam suco de laranja Moro por 4 semanas. Após, os animais dos grupos D, DLP e DLM receberam injeção de doxorrubicina (20mg/kg, IP) e os animais dos grupos C, LP e LM receberam injeção de salina. Quarenta e oito horas após a injeção de doxorrubicina, os animais foram submetidos ao ecocardiograma, medida da pressão intraventricular esquerda e eutanásia para coleta de material biológico. Resultados: Os ratos tratados com doxorrubicina ganharam menos... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Doxorubicin is a widely used chemotherapy and very effective in the treatment of cancer, but it can lead to cardiotoxicity, which may limit it’s use. The mechanisms involved in the emergence of cardiotoxicity are multiple, but the increase of oxidative stress plays a fundamental role. Orange juice contains many compounds with antioxidant potential, such as flavonoids. The composition of orange juice may differ between orange varieties and this may lead to different biological effects such as increased antioxidant activity. Objective: To evaluate the influence of Pera (Citrus sinensis) and Moro (Citrus sinensis (L.) Osbeck) orange juice on doxorubicin-induced cardiotoxicity in rats. Material and Methods: We used 120 adult male Wistar rats, which were allocated into 6 groups: C, LP, LM, D, DLP, DLM. Groups C and D were given water with maltodextrin to equalize the amount of carbohydrate in the orange juices. The LP and DLP groups received Pera orange juice and the LM and DLM groups received Moro orange juice for 4 weeks. Afterwards, animals from groups D, DLP and DLM received doxorubicin injection (20mg / kg, PI) and animals from groups C, LP and LM received saline injection. Forty-eight hours after doxorubicin injection, the animals underwent echocardiography, left intraventricular pressure measurement and euthanasia for collection of biological material. Results: Doxorubicin-treated rats gained less weight than untreated rats, probably due to the decreased intak... (Complete abstract click electronic access below) / Mestre

The American Heart Association (AHA) estimates that at least one American will die from a coronary event every minute, costing over $150 billion in 2008 alone. Regenerating the myocardium of patients that survive the initial infarction has proven to be an elusive goal. A variety of factors - including the loss of contractile cells, inflammatory response following infarction, cardiac hypertrophy, and lack of suitable cues for progenitor cells - causes fibrosis in the heart and loss of cardiac function. This dissertation examines three drug delivery strategies aimed at improving conditions for cardiac regeneration: polyketal microspheres as non-inflammatory drug delivery vehicles; surface functionalization of microparticles with nitrilotriacetic acid-nickel (NTA-Ni) for non-covalent tethering of proteins; and using Hoechst-inspired ligands for targeting extracellular DNA in necrotic tissue.

Made available in DSpace on 2014-06-11T19:27:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-06-22Bitstream added on 2014-06-13T20:16:28Z : No. of bitstreams: 1 moreira_vo_me_botfm.pdf: 190794 bytes, checksum: 9b05d27dc86eef1c15b6f47a424567ca (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Em modelos experimentais de agressão cardíaca, a dificuldade de se estabelecer uma classificação in vivo do grau de disfunção ventricular tem restringido a realização de estudos longitudinais. O objetivo deste estudo foi identificar variáveis ecocardiográficas que definam graus de insuficiência cardíaca em ratos com estenose aórtica (EAo). Foram usados ratos Wistar (n=23), machos (90-100 g) submetidos à cirurgia para indução de EAo. O grupo controle consistiu de 12 animais. Após a constatação de taquipnéia, foi realizado o exame ecocardiográfico. A análise de agrupamento possibilitou separar os ratos com EAo em dois grupos distintos quanto à gravidade do acometimento cardíaco, que foram denominados de disfunção leve (n=13) e disfunção grave (n=9). Um animal não se agrupou em nenhum das classificações. Como resultado da função discriminante de Fisher, foi encontrado três grupos distintos quanto a função cardíaca: normal, leve e grave. Concluímos que a análise de agrupamento e a função discriminante de Fisher, desenvolvidas a partir de variáveis ecocardiográficas são úteis na classificação funcional de ratos portadores de estenose aórtica. / The difficulty to detect different degrees of heart dysfunction in laboratory animals, in vivo, has restricted longitudinal studies. The purpose of this study was to identify echocardiographic parameters that allow distinguishing different degrees of cardiac dysfunction in aortic banded rats. Wistar male rats (90-100 g) were subjected to aortic banding (n=23) or a sham operation (n=12). Echocardiogram was performed after animals presented tachypnea. The following echocardiographic parameters were evaluated to cluster rats into groups with similar characteristics using cluster analysis: absolute or relative to body weight values of left ventricular end-diastolic diameter (LVDD) and left atrial systolic diameter; left ventricular endsystolic diameter (LVSD); LV weight to body weight ratio (LVW/BW); three indexes of left ventricular shortening (endocardial fractional shortening, EFS; midwall FS, MFS; and posterior wall shortening velocity, PWSV); and ratio of early to late diastolic mitral inflow velocities (E/A). Fisher's discriminatory graphic technique was used to elaborate the criteria to classify new animals into different degrees of cardiac function. Cluster analysis allowed the clustering of aortic banded rats into two groups according to the degree of heart failure severity which were named as mild (n=13) and severe (n=9) stage of heart failure. In conclusion, cluster analysis and Fisher's technique using echocardiographic data allowed the classification of degrees of heart function in aorctic banded rats, in vivo.