B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.

Duration-controlled swimming exercise training induces cardiac hypertrophy in mice

Exercise training associated with robust conditioning can be useful for the study of molecular mechanisms underlying exercise-induced cardiac hypertrophy. A swimming apparatus is described to control training regimens in terms of duration, load, and frequency of exercise. Mice were submitted to 60- vs 90-min session/day, once vs twice a day, with 2 or 4% of the weight of the mouse or no workload attached to the tail, for 4 vs 6 weeks of exercise training. Blood pressure was unchanged in all groups while resting heart rate decreased in the trained groups (8-18%). Skeletal muscle citrate synthase activity, measured spectrophotometrically, increased (45-58%) only as a result of duration and frequency-controlled exercise training, indicating that endurance conditioning was obtained. In groups which received duration and endurance conditioning, cardiac weight (14-25%) and myocyte dimension (13-20%) increased. The best conditioning protocol to promote physiological hypertrophy, our primary goal in the present study, was 90 min, twice a day, 5 days a week for 4 weeks with no overload attached to the body. Thus, duration- and frequency-controlled exercise training in mice induces a significant conditioning response qualitatively similar to that observed in humans.

Salt-induced epithelial-to-mesenchymal transition in Dahl salt-sensitive rats is dependent on elevated blood pressure

Dietary salt intake has been linked to hypertension and cardiovascular disease. Accumulating evidence has indicated that salt-sensitive individuals on high salt intake are more likely to develop renal fibrosis. Epithelial-to-mesenchymal transition (EMT) participates in the development and progression of renal fibrosis in humans and animals. The objective of this study was to investigate the impact of a high-salt diet on EMT in Dahl salt-sensitive (SS) rats. Twenty-four male SS and consomic SS-13BN rats were randomized to a normal diet or a high-salt diet. After 4 weeks, systolic blood pressure (SBP) and albuminuria were analyzed, and renal fibrosis was histopathologically evaluated. Tubular EMT was evaluated using immunohistochemistry and real-time PCR with E-cadherin and alpha smooth muscle actin (α-SMA). After 4 weeks, SBP and albuminuria were significantly increased in the SS high-salt group compared with the normal diet group. Dietary salt intake induced renal fibrosis and tubular EMT as identified by reduced expression of E-cadherin and enhanced expression of α-SMA in SS rats. Both blood pressure and renal interstitial fibrosis were negatively correlated with E-cadherin but positively correlated with α-SMA. Salt intake induced tubular EMT and renal injury in SS rats, and this relationship might depend on the increase in blood pressure.

A combination of methylprednisolone and quercetin is effective for the treatment of cardiac contusion following blunt chest trauma in rats

Cardiac contusion is a potentially fatal complication of blunt chest trauma. The effects of a combination of quercetin and methylprednisolone against trauma-induced cardiac contusion were studied. Thirty-five female Sprague-Dawley rats were divided into five groups (n=7) as follows: sham, cardiac contusion with no therapy, treated with methylprednisolone (30 mg/kg on the first day, and 3 mg/kg on the following days), treated with quercetin (50 mg·kg−1·day−1), and treated with a combination of methylprednisolone and quercetin. Serum troponin I (Tn-I) and tumor necrosis factor-alpha (TNF-α) levels and cardiac histopathological findings were evaluated. Tn-I and TNF-α levels were elevated after contusion (P=0.001 and P=0.001). Seven days later, Tn-I and TNF-α levels decreased in the rats treated with methylprednisolone, quercetin, and the combination of methylprednisolone and quercetin compared to the rats without therapy, but a statistical significance was found only with the combination therapy (P=0.001 and P=0.011, respectively). Histopathological degeneration and necrosis scores were statistically lower in the methylprednisolone and quercetin combination group compared to the group treated only with methylprednisolone (P=0.017 and P=0.007, respectively). However, only degeneration scores were lower in the combination therapy group compared to the group treated only with quercetin (P=0.017). Inducible nitric oxide synthase positivity scores were decreased in all treatment groups compared to the untreated groups (P=0.097, P=0.026, and P=0.004, respectively). We conclude that a combination of quercetin and methylprednisolone can be used for the specific treatment of cardiac contusion.

Étude de la fonction vasculaire et du remodelage cardiaque avant l’établissement de l’obésité et de la dyslipidémie chez les rats femelles Sprague-Dawley recevant une diète riche en gras

Des lacunes existent au niveau des connaissances concernant les modifications cardiovasculaires manifestées avant l’établissement d’obésité et en absence d’hyperlipidémie. Dans cette optique, la présente étude a testé l'hypothèse générale qui stipule que l’administration d’une diète riche en gras pour une période de 8 semaines chez les rats femelles influence négativement la fonction et le remodelage cardiaque, avant le développement de l’obésité et en absence d’hyperlipidémie et d’hyperglycémie. Afin de répondre à cette problématique, des rats femelles Sprague-Dawley ont été assignés à une diète standard (SD; 12,5% lipides, kcal) ou riche en gras (HF; 42% lipides, kcal) pour une période de 8 semaines. Cette durée était insuffisante pour induire le développement d’une dyslipidémie ou une augmentation significative de la masse corporelle chez les animaux HF(329±14g) comparativement aux rates SD (300±10g). Toutefois, une hypertension artérielle s’est développée chez les rates HF (130±4 vs 108±6 mmHg, p<0,05), accompagnée d’une altération des relaxations aortiques dépendantes de l’endothélium (relaxation maximale : 22±5% versus 53±8%, pour les animaux HF et SD respectivement, p<0,05). L’administration orale chronique de l’antioxydant resvératrol (RES; 20 mg·kg-1·jr-1) a prévenu le développement de ces altérations pathologiques, attestant d’une implication du stress oxydant. Au niveau cardiaque, le RES n’a toutefois pas inhibé le développement de fibrose périvasculaire secondaire à l’administration de la diète riche en gras. Suite à une insulte d’ischémie-reperfusion, la taille (SD : 0,29±0,09 versus HF : 0,32±0,13 cm), l’épaisseur (SD : 0,05±0,02 versus HF : 0,06±0,01 cm) et le contenu en collagène α1 type 1 (SD : 0,21±0,04 versus HF : 0,20±0,04 unités arbitraires/mm2) de la cicatrice du coeur infarci des rats HF étaient comparables au coeur infarci des rats SD. Malgré ces similitudes, le taux de décès était significativement (p<0,05) plus élevé chez les rats HF (56%) comparativement aux rats SD (5%). L’approche par électrophysiologie a démontré que l’administration de la diète riche en gras était associée à une augmentation (p<0,05) du nombre d’extrasystoles ventriculaires induites. Cette élévation de l’incidence était associé à une hyperinnervation sympathique fonctionnelle, tel que démontré par une élévation (p<0,05) de la densité des fibres neurofilament-M (HF : 2830±250 versus SD : 2020±260 μm2/mm2) et de la protéine de l’hydroxylase de la tyrosine. La fonctionnalité des jonctions intercellulaires était également atteinte, caractérisée par une latéralisation et internalisation de connexine 43 ainsi qu’une diminution de l’expression de connexine 40 au niveau des disques intercalaires. Ainsi, avant l’établissement de l’obésité et d’une dyslipidémie, les rats femelles modestement hypertendus présentent un phénotype arythmogénique cardiaque en partie dû à une hyperinnervation sympathique et une expression altérée concomitante de la distribution et de l’expression des jonctions intercellulaires. L’absence de symptômes cliniques d’obésité dans la présente étude ne fournit aucun indice au clinicien quant à la susceptibilité accrue aux arythmies ventriculaires. Ainsi, en présence d’une hypertension artérielle modérée chez un patient non-obèse, une mesure de l’activité sympathique par la quantification des niveaux circulants de catécholamines pourrait être bénéfique afin de détecter les patients à risque de mort subite.

Role of Nuclear Angiotensin-II Receptor Mediated Signalling in Cardiovascular Remodelling

Le remodelage cardiaque est le processus par lequel la structure ou la fonction cardiaque change en réponse à un déséquilibre pathophysiologique tel qu'une maladie cardiaque, un contexte d'arythmie prolongée ou une modification de l'équilibre hormonal. Le système rénine-angiotensine (SRA) est un système hormonal largement étudié et il est impliqué dans de nombreuses activités associées au remodelage cardiovasculaire. L’existence d'un système circulatoire couplé à un système de tissus locaux est une représentation classique, cependant de nouvelles données suggèrent un SRA indépendant et fonctionnellement actif à l'échelle cellulaire. La compréhension de l'activité intracellulaire du SRA pourrait mener à de nouvelles pistes thérapeutiques qui pourraient prévenir un remodelage cardiovasculaire défavorable. L'objectif de cette thèse était d'élucider le rôle du SRA intracellulaire dans les cellules cardiaques. Récemment, les récepteurs couplés aux protéines G (RCPG), les protéines G et leurs effecteurs ont été détectés sur des membranes intracellulaires, y compris sur la membrane nucléaire, et les concepts de RCPG intracellulaires fonctionnels sont en voie d'être acceptés comme une réalité. Nous avons dès lors fait l'hypothèse que la signalisation du SRA délimitant le noyau était impliquée dans le contrôle de l'expression des gènes cardiaques. Nous avons démontré la présence de récepteurs d'angiotensine de type-1 (AT1R) et de type-2 (AT2R) nucléaires dans les cardiomyocytes ventriculaires adultes et dans une fraction nucléaire purifiée de tissu cardiaque. Des quantités d'Ang II ont été détectées dans du lysat de cardiomyocytes et des microinjections d'Ang-II-FITC ont donné lieu à des liaisons préférentielles aux sites nucléaires. L'analyse transcriptionnelle prouve que la synthèse d'ARN de novo dans des noyaux isolés stimulés à l'Ang-II, et l'expression des ARNm de NF-κB étaient beaucoup plus importants lorsque les noyaux étaient exposés à de l'Ang II par rapport aux cardiomyocytes intacts. La stimulation des AT1R nucléaires a engendré une mobilisation de Ca2+ via les récepteurs de l'inositol trisphosphate (IP3R), et le blocage des IP3R a diminué la réponse transcriptionnelle. Les méthodes disponibles actuellement pour l'étude de la signalisation intracrine sont limitées aux méthodes indirectes. L'un des objectifs de cette thèse était de synthétiser et caractériser des analogues d'Ang-II cellule-perméants afin d’étudier spécifiquement dans les cellules intactes l'activité intracellulaire du SRA. Nous avons synthétisé et caractérisé pharmacologiquement des analogues photosensibles Ang-II encapsulée en incorporant un groupement 4,5-diméthoxy-2-nitrobenzyl (DMNB) photoclivable sur les sites actifs identifiés du peptide. Chacun des trois analogues d'Ang II encapsulée synthétisés et purifiés: [Tyr(DMNB)4]Ang-II, Ang-II-ODMNB et [Tyr(DMNB)4]Ang-II-ODMNB a montré une réduction par un facteur deux ou trois de l'affinité de liaison envers AT1R et AT2R dans les dosages par liaison compétitive et une activité réduite dans la contraction de l'aorte thoracique. La photostimulation de [Tyr(DMNB)4]Ang-II dans des cellules HEK a augmenté la phosphorylation d'ERK1/2 (via AT1R) et la production de cGMP (via AT2R) alors que dans les cardiomyocytes isolés elle générait une augmentation de Ca2+ nucléoplasmique et initiait la synthèse d'ARNr 18S et d'ARNm du NF-κB. Les fibroblastes sont les principaux générateurs de remodelage cardiaque structurel, et les fibroblastes auriculaires sont plus réactifs aux stimuli profibrotiques que les fibroblastes ventriculaires. Nous avons émis l'hypothèse que l’Ang-II intracellulaire et l'activation des AT1R et AT2R nucléaires associés contrôlaient les profils d'expression des gènes des fibroblastes via des systèmes de signalisation distincts et de ce fait jouaient un rôle majeur dans le développement de la fibrose cardiaque. Nous avons remarqué que les fibroblastes auriculaires expriment l’AT1R et l’AT2R nucléaire et l'Ang-II au niveau intracellulaire. L’expression d'AT1R nucléaire a été régulés positivement dans les cas d’insuffisance cardiaque (IC), tandis que l'AT2R nucléaire a été glycosylé post-traductionnellement. La machinerie protéique des protéines G, y compris Gαq/11, Gαi/3, et Gβ, a été observée dans des noyaux isolés de fibroblastes. AT1R et AT2R régulent l'initiation de la transcription du fibroblaste via les voies de transduction de signal d'IP3R et du NO. La photostimulation de [Tyr(DMNB)4]Ang-II dans une culture de fibroblastes auriculaire déclenche la libération de Ca2+ nucléoplasmique, la prolifération, et la synthèse et sécrétion de collagène qui ne sont pas inhibées par les bloqueurs d'AT1R et/ou AT2R extracellulaires.

Regulation of bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential.

Cardiac myocyte apoptosis is potentially important in many cardiac disorders. In other cells, Bcl-2 family proteins and mitochondrial dysfunction are probably key regulators of the apoptotic response. In the present study, we characterized the regulation of antiapoptotic (Bcl-2, Bcl-xL) and proapoptotic (Bad, Bax) Bcl-2 family proteins in the rat heart during development and in oxidative stress-induced apoptosis. Bcl-2 and Bcl-xL were expressed at high levels in the neonate, and their expression was sustained during development. In contrast, although Bad and Bax were present at high levels in neonatal hearts, they were barely detectable in adult hearts. We confirmed that H(2)O(2) induced cardiac myocyte cell death, stimulating poly(ADP-ribose) polymerase proteolysis (from 2 hours), caspase-3 proteolysis (from 2 hours), and DNA fragmentation (from 8 hours). In unstimulated neonatal cardiac myocytes, Bcl-2 and Bcl-xL were associated with the mitochondria, but Bad and Bax were predominantly present in a crude cytosolic fraction. Exposure of myocytes to H(2)O(2) stimulated rapid translocation of Bad (<5 minutes) to the mitochondria. This was followed by the subsequent degradation of Bad and Bcl-2 (from approximately 30 minutes). The levels of the mitochondrial membrane marker cytochrome oxidase remained unchanged. H(2)O(2) also induced translocation of cytochrome c from the mitochondria to the cytosol within 15 to 30 minutes, which was indicative of mitochondrial dysfunction. Myocytes exposed to H(2)O(2) showed an early loss of mitochondrial membrane potential (assessed by fluorescence-activated cell sorter analysis) from 15 to 30 minutes, which was partially restored by approximately 1 hour. However, a subsequent irreversible loss of mitochondrial membrane potential occurred that correlated with cell death. These data suggest that the regulation of Bcl-2 and mitochondrial function are important factors in oxidative stress-induced cardiac myocyte apoptosis.

Blockage of Angiotensin II type 2 receptor prevents thyroxine-mediated cardiac hypertrophy by blocking Akt activation

Although most of effects of Angiotensin II (Ang II) related to cardiac remodelling can be attributed to type 1 Ang II receptor (AT(1)R), the type 2 receptor (AT(2)R) has been shown to be involved in the development of some cardiac hypertrophy models. In the present study, we investigated whether the thyroid hormone (TH) action leading to cardiac hypertrophy is also mediated by increased Ang II levels or by change on AT(1)R and AT(2)R expression, which could contribute to this effect. In addition, we also evaluated the possible contribution of AT(2)R in the activation of Akt and in the development of TH-induced cardiac hypertrophy. To address these questions, Wistar rats were treated with thyroxine (T(4), 0.1 mg/kg BW/day, i.p.), with or without AT(2)R blocker (PD123319), for 14 days. Cardiac hypertrophy was identified based on heart/body weight ratio and confirmed by analysis of atrial natriuretic factor mRNA expression. Cardiomyocyte cultures were used to exclude the influence of TH-related hemodynamic effects. Our results demonstrate that the cardiac Ang II levels were significantly increased (80%, P < 0.001) as well as the AT(2)R expression (50%, P < 0.05) in TH-induced cardiac hypertrophy. The critical involvement of AT(2)R to the development of this cardiac hypertrophy in vivo was evidenced after administration of AT(2) blocker, which was able to prevent in 40% (P < 0.01) the cardiac mass gain and the Akt activation induced by TH. The role of AT(2)R to the TH-induced cardiomyocyte hypertrophy was also confirmed after using PD123319 in the in vitro studies. These findings improve understanding of the cardiac hypertrophy observed in hyperthyroidism and provide new insights into the generation of future therapeutic strategies.

L-NAME Treatment Enhances Exercise-induced Content of Myocardial Heat Shock Protein 72 (Hsp72) in Rats

Background/Aim: Nitric oxide (NO) modulates the expression of the chaperone Hsp72 in the heart, and exercise stimulates both NO production and myocardial Hsp72 expression. The main purpose of the study was to investigate whether NO interferes with an exercise-induced myocardial Hsp72 expression. Methods: Male Wistar rats (70-100 days) were divided into control (C, n= 12), L-NAME-treated (L, n= 12), exercise (E, n= 13) and exercise plus L-NAME-treated (EL, n= 20) groups. L-NAME was given in drinking water (700 mg. L(-1)) and the exercise was performed on a treadmill (15-25 m.min(-1), 40-60 min. day(-1)) for seven days. Left ventricle (LV) protein Hsp content, NOS and phosphorylated-NOS (p-NOS) isoforms were measured using Western blotting. The activity of NOS was assayed in LV homogenates by the conversion of [(3)H] L-arginine to [(3)H] L-citrulline. Results: Hsp72 content was increased significantly (223%; p < 0.05) in the E group compared to the C group, but exercise alone did not alter the NOS content, p-NOS isoforms or NOS activity. Contrary to our expectation, L-NAME enhanced (p < 0.05) the exercise-induced Hsp72 content (EL vs. C, L and E groups = 1019%, 548% and 457%, respectively). Although the EL group had increased stimulatory p-eNOS(Ser1177) (over 200%) and decreased inhibitory p-nNOS(Ser852) (similar to 50%) compared to both the E and L groups (p < 0.05), NOS activity was similar in all groups. Conclusions: Our results suggest that exercise-induced cardiac Hsp72 expression does not depend on NO. Conversely, the in vivo L-NAME treatment enhances exercise-induced Hsp72 production. This effect may be due to an increase in cardiac stress. Copyright (C) 2011 S. Karger AG, Basel

Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3 beta/mTOR signaling pathway

Several studies have implicated the renin angiotensin system in the cardiac hypertrophy induced by thyroid hormone. However, whether Angiotensin type 1 receptor (AT(1)R) is critically required to the development of T(3)-induced cardiomyocyte hypertrophy as well as whether the intracellular mechanisms that are triggered by AT(1)R are able to contribute to this hypertrophy model is unknown. To address these questions, we employed a selective small interfering RNA (siRNA, 50 nM) or an AT(1)R blocker (Losartan, 1 mu M) to evaluate the specific role of this receptor in primary cultures of neonatal cardiomyocytes submitted to T(3) (10 nM) treatment. The cardiomyocytes transfected with the AT(1)R siRNA presented reduced mRNA (90%, P < 0.001) and protein (70%, P < 0.001) expression of AT(1)R. The AT(1)R silencing and the AT(1)R blockade totally prevented the T(3)-induced cardiomyocyte hypertrophy, as evidenced by lower mRNA expression of atrial natriuretic factor (66%, P < 0.01) and skeletal alpha-actin (170%, P < 0.01) as well as by reduction in protein synthesis (85%, P < 0.001). The cardiomyocytes treated with T(3) demonstrated a rapid activation of Akt/GSK-3 beta/mTOR signaling pathway, which was completely inhibited by the use of PI3K inhibitors (LY294002, 10 mu M and Wortmannin, 200 nM). In addition, we demonstrated that the AT(1)R mediated the T(3)-induced activation of Akt/GSK-3 beta/mTOR signaling pathway, since the AT(1)R silencing and the AT(1)R blockade attenuated or totally prevented the activation of this signaling pathway. We also reported that local Angiotensin I/II (Ang I/II) levels (120%, P < 0.05) and the AT(1)R expression (180%, P < 0.05) were rapidly increased by T(3) treatment. These data demonstrate for the first time that the AT(1)R is a critical mediator to the T(3)-induced cardiomyocyte hypertrophy as well as to the activation of Akt/GSK-3 beta/mTOR signaling pathway. These results represent a new insight into the mechanism of T(3)-induced cardiomyocyte hypertrophy, indicating that the Ang I/II-AT(1)R-Akt/GSK-3 beta/mTOR pathway corresponds to a potential mediator of the trophic effect exerted by T(3) in cardiomyocytes.

Effect of lycopene on doxorubicin-induced cardiotoxicity: An echocardiographic, histological and morphometrical assessment

Doxorubicin is an excellent chemotherapeutic agent utilized for several types of cancer but the irreversible doxorubicin-induced cardiac damage is the major limitation for its use. Oxidative stress seems to be associated with some phase of the toxicity mechanism process. To determine if lycopene protects against doxorubicin-induced cardiotoxicity, male Wistar rats were randomly assigned either to control, lycopene, doxorubicin or doxorubicin + lycopene groups. They received corn oil (control, doxorubicin) or lycopene (5 mg/kg body weight a day) (lycopene, doxorubicin + lycopene) by gavage for a 7-week period. They also received saline (control, lycopene) or doxorubicin (4 mg/kg) (doxorubicin, doxorubin + lycopene) intraperitoneally by week 3, 4 5 and 6. Animals underwent echocardiogram and were killed for tissue analyses by week 7. Mean lycopene levels (nmol/kg) in liver were higher in the doxorubicin + lycopene group (5822.59) than in the lycopene group (2496.73), but no differences in lycopene were found in heart or Plasma of these two groups. Lycopene did not prevent left ventricular systolic dysfunction induced by doxorubicin. However, morphologic examination revealed that doxorubicin-induced myocyte damage was significantly suppressed in rats treated with lycopene. Doxorubicin treatment was followed by increase of myocardium interstitial collagen volume fraction. Our results show that: (i) doxorubicin-induced cardiotoxicity was confirmed by echocardiogram and morphological evaluations; (ii) lycopene absorption was confirmed by its levels in heart, liver and plasma; (iii) lycopene supplementation provided myocyte protection without preventing interstitial collagen accumulation increase; (iv) doxorubicin-induced cardiac dysfunction was not prevented by lycopene supplementation; and (v) lycopene depletion was not observed in plasma and tissues from animals treated with doxorubicin.

Improved systolic ventricular function with normal myocardial mechanics in compensated cardiac hypertrophy

There is still controversy about the relation between changes in myocardial contractile function and global left ventricular (LV) performance during stable concentric hypertrophy. To clarify this, we analyzed LV function in vivo and myocardial mechanics in vitro in rats with pressure overload-induced cardiac hypertrophy. Male Wistar rats (70 g) Underwent ascending aortic stenosis for 8 weeks (group AAS, n = 9). LV performance wits assessed by transthoracic echocardiography Under anesthesia. Myocardial function Was studied in isolated papillary muscle preparations during isometric contraction. The data were compared with age- and sex-matched sham-operated rats (group C, 11 = 9). LV weight-to-body weight ratio (C: 2.13 +/- 0.14 mg/g; AAS: 3.24 +/- 0.44) LV relative wall thickness (C: 0.18 +/- 0.02; AAS: 0.33 +/- 0.09), and LV fractional shortening (C: 54 +/- 5%; AAS: 70 +/- 8%) were increased in group AAS (P<0.05). Echocardio-graphic analysis also indicated a significant association (r = 0.74 P<0.001) between the percent fractional shortening index and LV relative wall thickness. The performance of AAS isolated In muscle revealed that active tension (C: 6.6 +/- 1.7 g/mm(2); AAS: 6.5 +/- 1.5 g/mm(2)) and maximum rate of tension development (C: 69 +/- 21 g/mm(2)/s AAS: 69 +/- 18 g/mm(2)/s) were not significantly different Front group C (P>0.05). In conclusion, compensated pressure-overload myocardial hypertrophy is associated with preserved myocardial function and increased ventricular performance. The improved LV function might be due to the ventricular remodeling, characterized by an increased relative wall thickness.

Conjugated linoleic acid and cardiac health: Oxidative stress and energetic metabolism in standard and sucrose-rich diets

Studies on conjugated linoleic acid ingestion and its effect on cardiac tissue are necessary for the safe utilization of this compound as supplement for weight loss. Male Wistar 24-rats were divided into four groups (n = 6):(C)given standard chow, water and 0.5 ml saline, twice a week by gavage; (C-CLA)receiving standard chow, water and 0.5 ml of conjugated linoleic acid, twice a week, by gavage; (S)given standard chow, saline by gavage, and 30% sucrose in its drinking water; (S-CLA)receiving standard chow, 30% sucrose in its drinking water and conjugated linoleic acid. After 42 days of treatment S rats had obesity with increased abdominal-circumference, dyslipidemia, oxidative stress and myocardial lower citrate synthase(CS) and higher lactate dehydrogenase(LDH) activities than C. Conjugated linoleic acid had no effects on morphometric parameters in C-CLA, as compared to C, but normalized morphometric parameters comparing S-CLA with S. There was a negative correlation between abdominal adiposity and resting metabolic rate. Conjugated linoleic acid effect, enhancing fasting-VO2/surface area, postprandial-carbohydrate oxidation and serum lipid hydroperoxide resembled to that of the S group. Conjugated linoleic acid induced cardiac oxidative stress in both fed conditions, and triacylglycerol accumulation in S-CLA rats. Conjugated linoleic acid depressed myocardial LDH comparing C-CLA with C, and beta-hydroxyacyl-coenzyme-A dehydrogenase/CS ratio, comparing S-CLA with S. In conclusion, dietary conjugated linoleic acid supplementation for weight loss can have long-term effects on cardiac health. Conjugated linoleic acid, isomers c9, t11 and t10, c12 presented undesirable pro-oxidant effect and induced metabolic changes in cardiac tissue. Nevertheless, despite its effect on abdominal adiposity in sucrose-rich diet condition, conjugated linoleic acid may be disadvantageous because it can lead to oxidative stress and dyslipidemic profile. (c) 2007 Elsevier B.V All rights reserved.

Improved systolic ventricular function with normal myocardial mechanics in compensated cardiac hypertrophy

There still controversy about the relation between changes in myocardial contractile function and global left ventricular (LV) performance during stable concentric hypertrophy. To clarify this, we analyzed LV function in vivo and myocardial mechanics in vitro in rats with pressure overload-induced cardiac hypertrophy. Male Wistar rats (70 g) underwent ascending aorta stenosis for 8 weeks (group AAS, n=9). LV performance was assessed by transthoracic echocardiography under light anesthesia. Myocardial function was studied in isolated papillary muscle preparation during isometric contraction. The data were compared with age- and sex-matched sham-operated rats (group C, n=9). LV weight-to-body weight ratio (C: 2.0 ± 0.5 mg/g; AAS: 3.3 ± 0.7 mg/g), LV relative wall thickness (C: 0.19 ± 0.02; AAS; 0.34 ± 0.10), and LV fractional shortening (C: 54 ± 5%; AAS: 70 ± 8%) were increased in the group AAS (p<0.05). Echocardiographic analysis also indicated a significant association (r=0.74; p<0.001) between percent fractional shortening and LV relative wall thickness. The performance of AAS isolated muscle revealed that active tension (C: 6.6 ± 1.7 g/mm 2; AAS: 6.5 ± 1.5 g/mm 2) and maximum rate of tension development (C: 69 ± 21 g/mm 2/s; AAS: 69 ± 18 g/mm 2) were not significantly different from group C (p>0.05). In conclusion: 1) Compensated pressure-overload myocardial hypertrophy is associated with preserved myocardial function and increased ventricular performance; 2) The improved LV function might be due to the ventricular remodeling characterized by an increased relative wall thickness. Copyright © 2002 By PJD Publications Limited.

The Th17 pathway in the peripheral lung microenvironment interacts with expression of collagen V in the late state of experimental pulmonary fibrosis

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