Influência do antioxidante quercetina sobre a remodelação cardíaca e a atividade oxidativa de ratos com Diabetes mellitus

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Mecanismos envolvidos na cardiotoxidade aguda induzida pela doxorrubicina em ratos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Relação entre diferentes períodos da exposição à obesidade induzida por dieta e lipotoxidade cardíaca: papel do eixo Leptina/OB0R/AMPK/ACC/Malonil CoA

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Diabetes mellitus activates fetal gene program and intensifies cardiac remodeling and oxidative stress in aged spontaneously hypertensive rats

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

The Role of Lipotoxicity in Smoke Cardiomyopathy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Expressão das proteínas envolvidas no trânsito de cálcio miocárdico de ratos obesos por dieta hiperlipídica saturada

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Pamidronate attenuates diastolic dysfunction induced by myocardial infarction associated with changes in geometric patterning

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Acute doxorubicin-induced cardiotoxicity is associated with matrix metalloproteinase-2 alterations in rats

Background: Doxorubicin can cause cardiotoxicity. Matrix metalloproteinases (MMP) are responsible for degrading extracellular matrix components which play a role in ventricular dilation. Increased MMP activity occurs after chronic doxorubicin treatment. In this study we evaluated in vivo and in vitro cardiac function in rats with acute doxorubicin treatment, and examined myocardial MMP and inflammatory activation, and gene expression of proteins involved in myocyte calcium transients. Methods: Wistar rats were injected with doxorubicin (Doxo, 20 mg/kg) or saline (Control). Echocardiogram was performed 48 h after treatment. Myocardial function was assessed in vitro in Langendorff preparation. Results: In left ventricle, doxorubicin impaired fractional shortening (Control 0.59 +/- 0.07; Doxo 0.51 +/- 0.05; p < 0.001), and increased isovolumetric relaxation time (Control 20.3 +/- 4.3; Doxo 24.7 +/- 4.2 ms; p = 0.007) and myocardial passive stiffness. MMP-2 activity, evaluated by zymography, was increased in Doxo (Control 141338 +/- 8924; Doxo 188874 +/- 7652 arbitrary units; p < 0.001). There were no changes in TNF-alpha, INF-gamma, IL-10, and ICAM-1 myocardial levels. Expression of phospholamban, Serca-2a, and ryanodine receptor did not differ between groups. Conclusion: Acute doxorubicin administration induces in vivo left ventricular dysfunction and in vitro increased myocardial passive stiffness in rats. Cardiac dysfunction is related to myocardial MMP-2 activation. Increased inflammatory stimulation or changed expression of the proteins involved in intracellular calcium transients is not involved in acute cardiac dysfunction.

The effect of non-antihypertensive doses of angiotensin converting enzyme inhibitor on myocardial necrosis and hypertrophy in young rats with renovascular hypertension

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1. 0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n = 10). Myocardial histology was analysed in 3 microm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

Reproducibility of heart rate and rating of perceived exertion values obtained from different incremental treadmill tests

Objective The present study aimed to examine the reproducibility of heart rate (HR) and rating of perceived exertion (RPE) values obtained during different incremental treadmill tests. Equipment and methods Twenty male, recreational, endurance-trained runners (10-km running pace: 10–15 km·h−1) performed, in a counterbalanced order, three continuous incremental exercise tests with different speed increments (0.5 km·h−1, 1 km·h−1 and 2 km·h−1). Thereafter, each participant performed the three tests again, maintaining the same order as before. The reproducibility of the HR and RPE values were analyzed for all protocols during submaximal intensities (8, 10, 12, and 14 km·h−1). In addition, it was examined the reproducibility of maximal HR (HRmax) and peak RPE (RPEpeak). Results The variability of both the HR and RPE values showed a tendency to decrease over the stages during the incremental test and was not or slightly influenced by the incremental test design. The HR at 14 km·h−1 and HRmax presented the highest reproducibility (CV < 2%). In contrast, the submaximal RPE values showed higher variability indices (i.e., CV > 5.0%). In conclusion, the HR values were highly reproducible during the stages of the incremental test, in contrast to the RPE values that presented limited reproducibility.

Inibição sistêmica da NADPH oxidase: estudo do coração de ratos espontaneamente hipertensos com diabetes mellitus

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Inibição sistêmica da NADPH oxidase: estudo do coração de ratos espontaneamente hipertensos com diabetes mellitus

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Focal adhesion kinase governs cardiac concentric hypertrophic growth by activating the AKT and mTOR pathways

The heart responds to sustained overload by hypertrophic growth in which the myocytes distinctly thicken or elongate on increases in systolic or diastolic stress. Though potentially adaptive, hypertrophy itself may predispose to cardiac dysfunction in pathological settings. The mechanisms underlying the diverse morphology and outcomes of hypertrophy are uncertain. Here we used a focal adhesion kinase (FAK) cardiac-specific transgenic mice model (FAK-Tg) to explore the function of this non-receptor tyrosine kinase on the regulation of myocyte growth. FAK-Tg mice displayed a phenocopy of concentric cardiac hypertrophy, reflecting the relative thickening of the individual myocytes. Moreover, FAK-Tg mice showed structural, functional and molecular features of a compensated hypertrophic growth, and preserved responses to chronic pressure overload. Mechanistically, FAK overexpression resulted in enhanced myocardial FAK activity, which was proven by treatment with a selective FAK inhibitor to be required for the cardiac hypertrophy in this model. Our results indicate that upregulation of FAK does not affect the activity of Src/ERK1/2 pathway, but stimulated signaling by a cascade that encompasses PI3K, AKT, mTOR, S6K and rpS6. Moreover, inhibition of the mTOR complex by rapamycin extinguished the cardiac hypertrophy of the transgenic FAK mice. These findings uncover a unique role for FAK in regulating the signaling mechanisms that governs the selective myocyte growth in width, likely controlling the activity of PI3K/AKT/mTOR pathway, and suggest that FAK activation could be important for the adaptive response to increases in cardiac afterload. This article is part of a Special Issue entitled "Local Signaling in Myocytes". (C) 2011 Elsevier Ltd. All rights reserved.

SMALL INTERFERING RNA TARGETING FOCAL ADHESION KINASE PREVENTS CARDIAC DYSFUNCTION IN ENDOTOXEMIA

Sepsis and septic shock are associated with cardiac depression. Cardiovascular instability is a major cause of death in patients with sepsis. Focal adhesion kinase (FAK) is a potential mediator of cardiomyocyte responses to oxidative and mechanical stress. Myocardial collagen deposition can affect cardiac compliance and contractility. The aim of the present study was to determine whether the silencing of FAK is protective against endotoxemia-induced alterations of cardiac structure and function. In male Wistar rats, endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (10 mg/kg). Cardiac morphometry and function were studied in vivo by left ventricular catheterization and histology. Intravenous injection of small interfering RNA targeting FAK was used to silence myocardial expression of the kinase. The hearts of lipopolysaccharide-injected rats showed collagen deposition, increased matrix metalloproteinase 2 activity, and myocyte hypertrophy, as well as reduced 24-h +dP/dt and -dP/dt, together with hypotension, increased left ventricular end-diastolic pressure, and elevated levels of FAK (phosphorylated and unphosphorylated). Focal adhesion kinase silencing reduced the expression and activation of the kinase in cardiac tissue, as well as protecting against the increased collagen deposition, greater matrix metalloproteinase 2 activity, and reduced cardiac contractility that occur during endotoxemia. In conclusion, FAK is activated in endotoxemia, playing a role in cardiac remodeling and in the impairment of cardiac function. This kinase represents a potential therapeutic target for the protection of cardiac function in patients with sepsis.

Myocardial Remodeling after Large Infarcts in Rat Converts Post Rest-Potentiation in Force Decay

Background: Post-rest contraction (PRC) of cardiac muscle provides indirect information about the intracellular calcium handling. Objective: Our aim was to study the behavior of PRC, and its underlying mechanisms, in rats with myocardial infarction. Methods: Six weeks after coronary occlusion, the contractility of papillary muscles (PM) obtained from sham-operated (C, n = 17), moderate infarcted (MMI, n = 10) and large infarcted (LMI, n = 14) rats was evaluated, following rest intervals of 10 to 60 seconds before and after incubation with lithium chloride (Li+) substituting sodium chloride or ryanodine (Ry). Protein expression of SR Ca(2+)-ATPase (SERCA2), Na+/Ca2+ exchanger (NCX), phospholamban (PLB) and phospho-Ser(16)-PLB were analyzed by Western blotting. Results: MMI exhibited reduced PRC potentiation when compared to C. Opposing the normal potentiation for C, post-rest decays of force were observed in LMI muscles. In addition, Ry blocked PRC decay or potentiation observed in LMI and C; Li+ inhibited NCX and converted PRC decay to potentiation in LMI. Although MMI and LMI presented decreased SERCA2 (72 +/- 7% and 47 +/- 9% of Control, respectively) and phospho-Ser(16)-PLB (75 +/- 5% and 46 +/- 11%, respectively) protein expression, overexpression of NCX (175 +/- 20%) was only observed in LMI muscles. Conclusion: Our results showed, for the first time ever, that myocardial remodeling after MI in rats may change the regular potentiation to post-rest decay by affecting myocyte Ca(2+) handling proteins. (Arq Bras Cardiol 2012;98(3):243-251)