Mindin (Spondin 2) is a highly conserved extracellular matrix protein of the Mindin-F-spondin family and a regulator of host innate immunity. Despite its expression in the heart, its role in cardiac stress response is unknown. The objective of this study was to determine the role of mindin following myocardial infarction (MI). C57/BL6 wild-type (mindin+/+) or mindin knockout (mindin-/-) mice were randomized to permanent left anterior descending (LAD) coronary artery ligation or sham operation. Mindin expression level increased maximally on day 7 post MI, but returned to baseline by day 28. Mindin-/- mice showed reduced mortality, rupture rate, cardiac MMP-9/-2 activities, NF-kB activation, cytokines and macrophage recruitment. We concluded that mindin is a significant contributor to mortality and acute adverse remodeling post MI, partly through its unique attributes of innate immune regulator and inhibitor of angiogenesis. Mindin may function as a potential biomarker or therapeutic target post MI.

Mindin (Spondin 2) is a highly conserved extracellular matrix protein of the Mindin-F-spondin family and a regulator of host innate immunity. Despite its expression in the heart, its role in cardiac stress response is unknown. The objective of this study was to determine the role of mindin following myocardial infarction (MI). C57/BL6 wild-type (mindin+/+) or mindin knockout (mindin-/-) mice were randomized to permanent left anterior descending (LAD) coronary artery ligation or sham operation. Mindin expression level increased maximally on day 7 post MI, but returned to baseline by day 28. Mindin-/- mice showed reduced mortality, rupture rate, cardiac MMP-9/-2 activities, NF-kB activation, cytokines and macrophage recruitment. We concluded that mindin is a significant contributor to mortality and acute adverse remodeling post MI, partly through its unique attributes of innate immune regulator and inhibitor of angiogenesis. Mindin may function as a potential biomarker or therapeutic target post MI.

Background: Myocardial infarction (MI) results in severe biochemical, physiological, and cellular changes that lead to alterations in the structure and function of the myocardium. Oxidative stress potentiates this remodeling response and is associated with progressive worsening of cardiac function. Accordingly, we used a powerful antioxidant-based therapeutic strategy to improve cardiac health and study redox-dependent signaling. Methods: MI was surgically induced in rats by ligating the left anterior descending coronary artery. Subgroups of MI rats received resveratrol (i.p., 10 mg/kg/day for 28 days beginning immediately post-MI). Cardiac histology and biochemical analyses of genes and proteins implicated in cardiac fibrosis, hypertrophy, and apoptosis, and redox-dependent signaling were analyzed. Results: As expected, MI resulted in profound structural changes to the myocardium. Further, we observed a sharp reduction in nuclear factor-erythroid 2-related factor 2 (Nrf2) and Krüppel-like factor 15 (KLF15), factors that are responsible for maintaining the endogenous antioxidant capacity and regulating cardiac gene expression, respectively. It is likely that disruption of normal KLF15 signaling permitted the expression of several cardiac genes associated with progressive cardiac remodeling. Importantly, daily treatment with resveratrol ameliorated cardiac remodeling, improved redox state, restored Nrf2 expression, and up-regulated KLF15 expression. Further, induction of KLF15 signaling following resveratrol treatment is associated with attenuated expression of several genes implicated in cardiac remodeling. Conclusions: Chronic oxidative stress potentiates cardiac remodeling post-infarct, in part, by suppressing Nrf2 and KLF15 expression. Importantly, we demonstrate that normal KLF15 signaling may be rescued with an antioxidant-based therapy, which may be an attractive therapeutic target to support cardiac health post-MI.

Made available in DSpace on 2014-06-11T19:23:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-22Bitstream added on 2014-06-13T20:30:19Z : No. of bitstreams: 1 rafacho_bpm_me_botfm.pdf: 770961 bytes, checksum: 6adcd57ea96a701107db6a7e755e749f (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A exposição à fumaça do cigarro resulta em remodelação cardíaca e está relacionada com disfunção ventricular. A atenuação da remodelação cardíaca pode ser importante para melhor prognóstico cardiovascular. A vitamina D (VD) tem se destacado por seu papel na função cardíaca e por atenuar a remodelação cardíaca em modelos de sobrecarga de pressão ou de volume. Objetivo: avaliar a influência da suplementação de VD sobre a remodelação cardíaca induzida pela exposição à fumaça do cigarro (EFC) em ratos, se a VD atua de forma dose dependente e verificar se esta atuação é por mecanismos anti-inflamatórios ou antioxidantes. Métodos: Ratos machos Wistar com 200 a 250g foram alocados em seis grupos: 1) VD0-NEFC, sem suplementação de VD e não EFC; 2) VD1-NEFC, suplementação de 1000 UI VD/kg de ração e não EFC (n=8); 3) VD3-NEFC, suplementação com 3000 UI VD/kg de ração e não EFC; 4) VD0-EFC, sem suplementação de VD e EFC; 5) VD1-EFC, suplementação de 1000 UI VD/kg de ração e EFC; 6) VD3-EFC, suplementação de 3000 UI VD/kg de ração e EFC. Após dois meses, os animais foram submetidos à ecocardiografia e eutanasiados para coleta de material biológico. Foram avaliados porcentagem de colágeno, área seccional do miócito (ASM), estresse oxidativo e marcadores inflamatórios no tecido cardíaco e dosagens sanguíneas de cálcio, fósforo e do metabólito 25-hidroxicolecalciferol. Os dados foram analisados por ANOVA de duas vias e apresentados em media ± erro-padrão. Foi utilizado teste de tendência (correlação de Spearman) para avaliar a resposta de dose dependência. Resultados: a EFC promoveu maior valor de parede posterior do ventrículo esquerdo (EFC = 1,38 ± 0,03; NEFC = 1,26 ± 0,03; p = 0,009), maior diâmetro diastólico do VE corrigido pela tíbia (EFC = 17,7 ± 0,20; NEFC = 17,0 ± 0,002; p = 0,033), maior massa do VE (MVE)... / Exposure to tobacco smoke (ETS) results in cardiac remodeling and it is associated with ventricular dysfunction. Attenuation of cardiac remodeling may be important for better cardiovascular prognosis. Vitamin D (VD) has become known for its role in cardiac function and VD supplementation attenuate cardiac remodeling in models of pressure or volume overload in previous studies. Objective: To evaluate the influence of VD supplementation on cardiac remodeling induced by ETS in rats and whether VD actions are dose-dependent and if these actions involve anti-inflammatory and antioxidant mechanisms. Methods: Male Wistar rats with 200 to 250g were allocated into six groups: 1) VD0- NETS, with no supplementation of VD and no ETS, 2)-VD1-NETS, supplementation with 1000 IU VD/kg of diet and no ETS (n = 8); 3) VD3-NETS, supplemented with 3000 IU VD/kg of diet and no ETS, 4) VD0-ETS, no supplementation of VD and ETS, 5)VD1-ETS, VD supplementation with 1000 IU/kg of diet and ETS, 6) VD3-ETS, VD supplementation of 3000 IU/kg of diet and ETS. After two months, the animals underwent echocardiography and euthanized for tissue collection. The collagen percentage, myocyte cross-sectional area (MCA), oxidative stress and inflammation biomarkers in cardiac tissue were determined. Blood levels of calcium, phosphorus and 25-hydroxycholecalciferol were also evaluated. Data were analyzed by two-way ANOVA and presented as mean ± standard error. Spearman correlation test was used to evaluate the dose dependent response. Results: ETS promoted greater value of left ventricular posterior wall (ETS = 1.38 ± 0.03; NETS = 1.26 ± 0.03, p = 0.009), LV diastolic diameter corrected by the tibia (ETS = 17.7 ± 0.20, 17.0 ± NETS = 0.002, p = 0.033), higher LV mass (LVM) (ETS = 603 ± 23; NETS = 509 ± 25, p = 0.007), higher LMV index (ETS = 1.8 ± 0.06; NETS = 1.5 ± 0.07, p = 0.004), increased MCA ... (Complete abstract click electronic access below)

Made available in DSpace on 2014-06-11T19:23:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-18Bitstream added on 2014-06-13T19:09:02Z : No. of bitstreams: 1 oliveirajr_sa_me_botfm.pdf: 1126092 bytes, checksum: 9767b89b53ffc12296fa5f7b701bc920 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Tem sido demonstrado que a obesidade promove remodelação cardíaca em ratos. Este estudo investigou a influência da obesidade induzida por dieta hipercalórica (HP) sobre as variáveis nutricionais e o remodelamento cardíaco, considerando a hipertrofia, fibrose intersticial e composição de cadeias pesadas de miosina (MHC), em ratos normotensos Wistar Kyoto (WKY) e ratos espontaneamente hipertensos (SHR). Parcelas de SHR (20) e WKY (20) com 60 dias de idade foram distribuídas em quatro grupos: SHR-C, SHR-OB, WKY-C e WKY-OB. Os grupos C receberam uma dieta normocalórica (C, 3,15 Kcal/g) e os grupos OB foram tratados com uma dieta hipercalórica (4,5 Kcal/g) durante 20 semanas. Dois critérios foram adotados para refinar a composição dos grupos em referência à obesidade, baseados na ingestão alimentar e no peso corporal (PC). As determinações nutricionais incluíram ingestão calórica, eficiência alimentar, PC, adiposidade, glicemia e perfil lipidêmico. A pressão arterial sistólica (PAS) foi mensurada antes e após a intervenção dietética. As análises morfológicas abrangeram a pesagem dos átrios, ventrículos direito e esquerdo e o estudo da umidade procedeu-se em fragmentos cardíacos, hepáticos e pulmonares. Secções histológicas miocárdicas foram utilizadas para cálculo da área seccional do miócito (AM) e fração intersticial de colágeno (FIC). A composição relativa de MHCs foi determinada por eletroforese de gel de poliacrilamida duodecil sulfato de sódio. A composição dos grupos foi submetida à análise estatística pelo teste de proporções binomiais entre e dentro das populações. Algumas variáveis nutricionais e a PAS foram analisadas por MANOVA no modelo de medidas repetidas. Os demais dados foram avaliados por ANOVA e teste de Tukey. Uma interação vigente entre linhagem e tratamento foi notada na composição dos grupos. / Obesity has been shown to induce cardiac remodeling in rats. In this study, we investigated the influence of obesity induced by high-fat diet (HFD) on nutritional variables and cardiac remodeling, concerning hypertrophy, interstitial fibrosis and myosin heavy chain composition, in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Sixty-day-old SHR (n=20) and WKY (n=20) were distributed into four groups: SHR-C, SHR-OB, WKY-C e WKY-OB. The C groups received a control diet (C, 3,15 Kcal/g) and the OB groups were treated with a HFD (4,5 Kcal/g) during 20 weeks. Two criteria were adopted to refine the groups composition in reference to obesity based on food consumption and body weight (BW). Nutritional determinations included energy intake, feed efficiency, BW, adiposity, glycemia and lipid profile. Systolic blood pressure (SBP) was measured before and after diet intervention. Morphological analysis involved atria, right and left ventricles weights and humidity study was realized with cardiac, liver and lung pieces. Using myocardial histological sections, myocyte cross sectional areas (MA) and collagen interstitial fraction (CIF) were measured. Relative myosin heavy chain (MHC) composition was determined using sodium dodecyl sulfatepolyacrylamide gel electrophoresis. The groups compositions were submitted to statistical analysis by the binomial proportional test between and within populations. Some nutritional variables and SBP were analyzed by two-way MANOVA in repeated measures model. Other data were evaluated by two-way ANOVA and Tukey test. An interaction between strain and treatment was noted to groups composition. Alimentar efficiency was increased only in the WKYOB and glycemic tolerance was impaired in both OB groups. HFD induced an increase of BW (WKY-C 481.6±39.4 g; WKY-OB 611.4±48.2 g; p<0.05; SHRC 370.3±16.0 g; SHR-OB 410.8±9.3 g; p<0.05) and adiposity in both strains.

Abstract Cardiac remodeling is defined as changes in the size, shape and function of the heart, caused most commonly by hypertension-induced left ventricular (LV) hypertrophy and myocardial infarction (MI). It is characterized by changes in cellular and extracellular compartments regulated by e.g. neurohumoral and inflammatory factors. In the present study the expression of novel, load induced factors, thrombospondin (TSP)-1 and -4, matrix Gla protein (MGP), tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14, was investigated during cardiac remodeling. Their expression in the heart was characterized using experimental models of pressure overload, hypertensive hypertrophy and MI, and the effect of hypertrophic agonists and cellular stretch was studied in vitro. The effect of beta-blocker treatment on TSP expression was also examined. TSP-1 and -4 were rapidly upregulated in response to pressure overload, and the induction of TSP-4 gene expression was attenuated in hypertrophied heart. After MI, TSP-1 and -4 mRNA and TSP-1 protein levels were increased, and the induction was attenuated by metoprolol. TSP-1 and -4 expression correlated with natriuretic peptide expression and LV remodeling after MI. In hypertensive hypertrophy, only TSP-4 expression decreased after metoprolol treatment and was correlated with LV remodeling. MGP gene expression was increased in response to pressure overload and MI both in the early and late phase of cardiac remodeling. MGP protein levels were increased in the acute phase of post-MI remodeling and in hypertensive hypertrophy. In vitro, angiotensin II increased MGP gene expression in myocytes and fibroblasts, whereas expression decreased in response to mechanical stretch. In response to increased cardiac load Fn14 expression was upregulated both acutely and chronically while TWEAK expression remained relatively constant. Fn14 localized mainly to fibroblasts in the inflammatory area while TWEAK localized to myocytes and endothelial cells. In myocytes, Fn14 expression was induced by hypertrophic agonists and mechanical stretch in contrast to stabile or decreased TWEAK expression. This study provides new insights into the expression of the studied novel factors in cardiac remodeling. The distinct expression of TSPs in pressure overload and post-MI suggests that TSP-1 and -4 may have unique roles in the remodeling process. The results also imply that MGP is part of the common gene program of hypertrophic remodeling in vivo and contributes to the molecular basis of cardiac hypertrophy. Finally, the study demonstrates differential regulation of TWEAK and Fn14 expression in the heart and emphasizes the importance of Fn14 as a mediator of TWEAK/Fn14 signaling and as a potential target of therapeutic interventions.

Cardiac remodeling involves changes in heart shape, size, structure, and function after injury to the myocardium. The proinflammatory adaptor protein myeloid differentiation protein 88 (MyD88) contributes to cardiac remodeling. To investigate whether excessive MyD88 levels initiate spontaneous cardiac remodeling at the whole-organism level, we generated a transgenic MyD88 mouse model with a cardiac-specific promoter. MyD88 mice (male, 20–30 g, n=~80) were born at the expected Mendelian ratio and demonstrated similar morphology of the heart and cardiomyocytes with that of wild-type controls. Although heart weight was unaffected, cardiac contractility of MyD88 hearts was mildly reduced, as shown by echocardiographic examination, compared with wild-type controls. Moreover, the cardiac dysfunction phenotype was associated with elevation of ANF and BNP expression. Collectively, our data provide novel evidence of the critical role of balanced MyD88 signaling in maintaining physiological function in the adult heart.

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

No description available.

Le peptide natriurétique de type B (BNP) est une hormone cardiaque fortement impliquée dans l'insuffisance cardiaque (IC). En clinique, le BNP est un bio-marqueur de diagnostic et de pronostic de l'IC; son taux sanguin augmentant avec la progression du remodelage cardiaque, de la dysfonction du ventricule gauche (VG) et des altérations du couplage excitation-contraction (CEC). Administré sous une forme recombinante, le nésiritide, pour ses effets hémodynamiques vasorelaxants, chez des patients en IC aiguë décompensée, il a montré des effets controversés avec un risque d'augmentation de la mortalité. Pour comprendre l'implication du BNP dans le remodelage cardiaque post-ischémique et son efficacité thérapeutique, nous avons étudié les effets cardiaques in vivo et sur le CEC d'un traitement chronique au BNP (0,03 µg/kg/min) sur deux groupes expérimentaux : i) des souris saines, Sham, pendant 14 jours et ii) des souris PMI (Post-Myocardial Infarction) en stade précoce, après ligature de l'artère coronaire gauche (pendant 7 et 14 jours). Chez les Sham, le BNP a engendré une suractivation du système nerveux sympathique, une hypertrophie cardiaque, des altérations électrophysiologiques in vivo et des mouvements calciques dans les cardiomyocytes du VG, à l'origine d'arythmies cellulaires et cardiaques. Les effets délétères du BNP ont été prévenus par une combinaison de ce traitement avec un β-bloqueur : le métoprolol. Chez les PMI, la supplémentation en BNP a réduit l'inotropisme positif précoce acquis par une modification des mouvements calciques, a accéléré l'apparition des altérations des protéines du CEC et la survenue des arythmies. Le BNP accélère la décompensation cardiaque et pourrait être à déconseiller, du moins en monothérapie, en traitement clinique. / BNP is a natriuretic peptide released in excess in the blood during heart failure (HF) to reduce blood volume and pressure. A recombinant form of human BNP, nesiritide, is used for patients with acute decompensated HF but deleterious cardiac effects have been reported. We aimed to investigate the cardiac effects of chronic BNP supplementation (0.03 µg/kg/min) on: i) healthy mice (Sham) for 14 days and ii) mice subjected to myocardial infarction (MI) induced by coronary artery ligation (PMI) for 7 (D7) and (D14) 14 days. Sham treated animals (Sham-BNP) showed an increase in ventricular arrhythmias occurrence in consequence of sympathetic tone increase and Ca2+ handling alterations observed at cellular and protein levels in the left ventricle (LV). Most of these effects were reduced in Sham-BNP by the selective beta1-adrenergic blocker metoprolol. In the PMI group, at early stages after ligation, we showed an increase in cardiomyocytes contraction and Ca2+ handling at D7 and D14. But this response was attenuated in PMI-BNP. In PMI, alterations in Ca2+ handling proteins, particularly SERCA2a and RyR2 appeared at D14 but not D7. But BNP supplementation accelerated these alterations which appeared since D7 in the PMI-BNP group, in parallel with spontaneous arrhythmias occurrence at D7. BNP infusion attenuates compensatory "inotropism" intrinsic to the LV cardiomyocytes and promotes arrhythmias. Our results show that BNP, at least in monotherapy, may be hazardous for the treatment of patients with decompensated HF.