Exercise Training Can Prevent Cardiac Hypertrophy Induced by Sympathetic Hyperactivity with Modulation of Kallikrein-Kinin Pathway and Angiogenesis

Sympathetic hyperactivity induces adverse effects in myocardial. Recent studies have shown that exercise training induces cardioprotection against sympathetic overload; however, relevant mechanisms of this issue remain unclear. We analyzed whether exercise can prevent pathological hypertrophy induced by sympathetic hyperactivity with modulation of the kallikrein-kinin and angiogenesis pathways. Male Wistar rats were assigned to non-trained group that received vehicle; non-trained isoproterenol treated group (Iso, 0.3 mg kg(-1) day(-1)); and trained group (Iso+Exe) which was subjected to sympathetic hyperactivity with isoproterenol. the Iso rats showed hypertrophy and myocardial dysfunction with reduced force development and relaxation of muscle. the isoproterenol induced severe fibrosis, apoptosis and reduced myocardial capillary. Interestingly, exercise blunted hypertrophy, myocardial dysfunction, fibrosis, apoptosis and capillary decreases. the sympathetic hyperactivity was associated with high abundance of ANF mRNA and beta-MHC mRNA, which was significantly attenuated by exercise. the tissue kallikrein was augmented in the Iso+Exe group, and kinin B-1 receptor mRNA was increased in the Iso group. Moreover, exercise induced an increase of kinin B-2 receptor mRNA in myocardial. the myocardial content of eNOS, VEGF, VEGF receptor 2, pAkt and Bcl-2 were increased in the Iso+Exe group. Likewise, increased expression of pro-apoptotic Bad in the Iso rats was prevented by prior exercise. Our results represent the first demonstration that exercise can modulate kallikrein-kinin and angiogenesis pathways in the myocardial on sympathetic hyperactivity. These findings suggest that kallikrein-kinin and angiogenesis may have a key role in protecting the heart.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)National Council for Scientific and TechnologicalUniv Nove Julho Uninove, Programa Posgrad Ciencias Reabilitacao, São Paulo, BrazilUniversidade Federal de São Paulo Unifesp, São Paulo, BrazilUniv São Paulo, São Paulo, BrazilUniv Nove Julho Uninove, Programa Posgrad Med, São Paulo, BrazilUniversidade Federal de São Paulo Unifesp, São Paulo, BrazilFAPESP: 2009/54225-8National Council for Scientific and Technological: 477458/2009-2National Council for Scientific and Technological: 479395/2012-8Web of Scienc

Cell therapy prevents structural, functional and molecular remodeling of remote non-infarcted myocardium

Background/objectives: Therapy using bone marrow (BM) cells has been tested experimentally and clinically due to the potential ability to restore cardiac function by regenerating lost myocytes or increasing the survival of tissues at risk after myocardial infarction (MI). in this study we aimed to evaluate whether BM-derived mononuclear cell (MNC) implantation can positively influence the post-MI structural remodeling, contractility and Ca(2+)-handling proteins of the remote non-infarcted tissue in rats.Methods and results: After 48 h of MI induction, saline or BM-MNC were injected. Six weeks later, MI scars were slightly smaller and thicker, and cardiac dilatation was just partially prevented by cell therapy. However, the cardiac performance under hemodynamic stress was totally preserved in the BM-MNC treated group if compared to the untreated group, associated with normal contractility of remote myocardium as analyzed in vitro. the impaired post-rest potentiation of contractile force, associated with decreased protein expression of the sarcoplasmic reticulum Ca2+-ATPase and phosphorylated-phospholamban and overexpression of Na(+)/Ca(2+) exchanger, were prevented by BM-MNC, indicating preservation of the Ca(2+) handling. Finally, pathological changes on remodeled remote tissue such as myocyte hypertrophy, interstitial fibrosis and capillary rarefaction were also mitigated by cell therapy.Conclusions: BM-MNC therapy was able to prevent cardiac structural and molecular remodeling after MI, avoiding pathological changes on Ca(2+)-handling proteins and preserving contractile behavior of the viable myocardium, which could be the major contributor to the improvements of global cardiac performance after cell transplantation despite that scar tissue still exists. (C) 2013 Elsevier Ireland Ltd. All rights reserved.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Med, São Paulo, BrazilUniv Estadual Campinas, Dept Struct & Funct Biol, Campinas, SP, BrazilUniv São Paulo, Inst Heart, BR-05508 São Paulo, BrazilUniv São Paulo, Inst Biomed Sci, BR-05508 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med, São Paulo, BrazilWeb of Scienc

Amelioration of Cardiac Function and Activation of Anti-Inflammatory Vasoactive Peptides Expression in the Rat Myocardium by Low Level Laser Therapy

Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. the present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. the potential participation of the Renin-Angiotensin System (RAS) and Kallikrein-Kinin System (KKS) vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. in addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF) in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. the mRNA expression of the inducible nitric oxide synthase (iNOS) was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx) concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO) generation.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Nove Julho, UNINOVE, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, São Paulo, BrazilUniv São Paulo, Heart Inst InCor, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, São Paulo, BrazilCNPq: 477458/2009-2CNPq: 309715/2011-3CNPq: 479395/2012-8: 2009/54225-8Web of Scienc

Exercise Attenuates Renal Dysfunction with Preservation of Myocardial Function in Chronic Kidney Disease

Previous studies have suggested that exercise improves renal and cardiac functions in patients with chronic kidney disease. the aim of this study was to evaluate the effects of long-term aerobic swimming exercise with overload on renal and cardiac function in rats with 5/6 nefrectomy (5/6Nx). Eight Wistar rats were placed into 4 groups: Control (C), Control+Exercise (E), Sedentary 5/6Nx (NxS) and 5/6Nx+Exercise (NxE). the rats were subjected to swimming exercise sessions with overload for 30 min five days per week for five weeks. Exercise reduced the effect of 5/6Nx on creatinine clearance compared to the NxS group. in addition, exercise minimized the increase in mean proteinuria compared to the NxS group (96.9 +/- 10.0 vs. 51.4 +/- 9.9 mg/24 h; p<0.05). Blood pressure was higher in the NxS and NxE groups compared to the C and E groups (216 +/- 4 and 178 +/- 3 vs. 123 +/- 2 and 124 +/- 2 mm Hg, p<0.05). in the 200 glomeruli that were evaluated, the NxS group had a higher sclerosis index than did the NxE group (16% vs. 2%, p<0.05). Echocardiography demonstrated a higher anterior wall of the left ventricle (LV) in diastole in the NxS group compared with the C, E and NxE groups. the NxS group also had a higher LV posterior wall in diastole and systole compared with the E group. the developed isometric tension in Lmax of the heart papillary muscle was lower in the NxS group compared with the C, E and NxE groups. These results suggested that exercise in 5/6Nx animals might reduce the progression of renal disease and lessen the cardiovascular impact of a reduction in renal mass.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundacao Oswaldo Ramos (FOR)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, UNIFESP EPM, Dept Med, Div Nephrol, São Paulo, BrazilUniversidade Federal de São Paulo, Cardiophysiol & Pathophysiol Lab, São Paulo, BrazilUniv São Paulo, Sch Med, Heart Inst InCor, Lab Genet & Mol Cardiol, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP EPM, Dept Med, Div Nephrol, São Paulo, BrazilUniversidade Federal de São Paulo, Cardiophysiol & Pathophysiol Lab, São Paulo, BrazilWeb of Scienc

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure &lt;= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Bone marrow cell therapy prevents infarct expansion and improves border zone remodeling after coronary occlusion in rats

Background: Since the cell therapy benefits for myocardial infarction are mainly related to infarct reduction by regenerating lost myocardium or increasing survival of tissues at risk, we evaluated the effects of bone marrow-derived mononuclear cells (MNC), implanted after the completion of necrosis, on infarct progression and cardiac remodeling. Methods: After 48 h of induction of myocardial infarction (MI), Lewis-inbred rats were injected with 6 x 10(6) cells (MI + MNC) or saline (MI). After six weeks, scar dimension, ventricular morphology and function were analyzed by echocardiography followed by histomorphology of the infarcted and border zones. Results: After therapy, the relative size of the infarct was smaller in MI + MNC (37 +/- 1% of the left ventricle) than in MI (43 +/- 1%). While the MI group exhibited parallel elongation of the infarcted (31.6 +/- 3.8% increase) and reminiscent ventricular portions (33.5 +/- 3.7%), MNC therapy preserved the initial infarct length. Infarcted walls were thicker (979 +/- 31 mm) in the MNC group than in the untreated group (709 +/- 41 mm), also demonstrating an absence of infarct expansion. In the border zones, MNC led to increased capillary densities and capillary/myocyte ratios. The cardiac systolic function remained depressed in MI, but improved by 19 +/- 5% in MI + MNC which reduced the incidence of pulmonary arterial hypertension (37.5% in MI and 6.25% in MI + MNC). Conclusion: MNC therapy prevented the infarct expansion and thinning related to cardiac remodeling and was associated with an improvement of border zone microcirculation: as a result, MNC therapy reduced typical MI dysfunctional repercussions. (C) 2009 Elsevier Ireland Ltd. All rights reserved.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP

The action of pre-exercise low-level laser therapy (LLLT) on the expression of IL-6 and TNF-alpha proteins and on the functional fitness of elderly rats subjected to aerobic training

The aim of the present study was to determine whether low-level laser therapy (LLLT), when used in conjunction with aerobic training, interferes with the expression of inflammatory markers IL-6 and TNF-alpha, thereby influencing the performance of old rats participating in swimming. A total of 30 Wistar rats (Rattus norvegicus albinus) were used for this study: 24 aged rats, and 6 young rats. the older animals were randomly divided into four groups designated as follows: aged-control, aged-exercise, aged-LLLT, aged-LLLT/exercise group, and young-control animals. Aerobic capacity (VO(2)max) was analyzed before and after training period. the aged-exercise and aged-LLLT/exercise groups were trained for 6 weeks. LLLT laser was applied before each training session with 808 nm and 4 J of energy to the indicated groups throughout training. the rats were euthanized, and muscle tissue and serum were collected for muscle cross-sectional area and IL-6 and TNF-alpha protein analysis. in VO2 showed statistical difference between young- and aged-control groups (used as baseline) (p < 0.05). the same difference can be observed in the young control group compared with all intervention groups (exercise, LLLT and LLLT + exercise). in comparison with the aged-control group, a difference was observed only for comparison with the exercise group (p < 0.05), and exercise associated with LLLT group (p < 0.001). Levels of IL-6 and TNF-alpha for the aged-exercise and the aged-LLLT/exercise groups were significantly decreased compared to the aged-control group (p < 0.05). Analysis of the transverse section of the gastrocnemius muscle showed a significant difference between the aged-exercise and aged-LLLT/exercise groups (p < 0.001). These results suggest that laser therapy in conjunction with aerobic training may provide a therapeutic approach for reducing the inflammatory markers (IL-6 and TNF-alpha), however, LLLT without exercise was not able to improve physical performance of aged rats.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ Nove Julho UNINOVE, Postgrad Program Biophoton Appl Hlth Sci, São Paulo, SP, BrazilUniv Nove Julho UNINOVE, Postgrad Program Rehabil Sci, São Paulo, SP, BrazilUniv Nove Julho UNINOVE, Postgrad Program Med, São Paulo, SP, BrazilUniversidade Federal de São Paulo, Dept Cardiol, São Paulo, SP, BrazilUniversidade Federal de São Paulo, Dept Cardiol, São Paulo, SP, BrazilFAPESP: 2009/54225-8Web of Scienc

Remodelamento Cardíaco e Expressão da ILK Diferem entre os Gêneros após Infarto do Miocárdio

Background: Gender can influence post-infarction cardiac remodeling. Objective: To evaluate whether gender influences left ventricular (LV) remodeling and integrin-linked kinase (ILK) after myocardial infarction (MI). Methods: Female and male Wistar rats were assigned to one of three groups: sham, moderate MI (size: 20-39% of LV area), and large MI (size: ≥40% of LV area). MI was induced by coronary occlusion, and echocardiographic analysis was performed after six weeks to evaluate MI size as well as LV morphology and function. Real-time RT-PCR and Western blot were used to quantify ILK in the myocardium. Results: MI size was similar between genders. MI resulted in systolic dysfunction and enlargement of end-diastolic as well as end-systolic dimension of LV as a function of necrotic area size in both genders. Female rats with large MI showed a lower diastolic and systolic dilatation than the respective male rats; however, LV dysfunction was similar between genders. Gene and protein levels of ILK were increased in female rats with moderate and large infarctions, but only male rats with large infarctions showed an altered ILK mRNA level. A negative linear correlation was evident between LV dimensions and ILK expression in female rats with large MI. Conclusions: Post-MI ILK expression is altered in a gender-specific manner, and higher ILK levels found in females may be sufficient to improve LV geometry but not LV function.Fundamento: O gênero pode ser decisivo no remodelamento cardíaco após infarto do miocárdio. Objetivo: Avaliar diferenças de gênero associadas ao remodelamento do ventrículo esquerdo (VE) após infarto do miocárdio (IM) e associadas à modulação de quinases acopladas à integrina (integrin-linked kinases-ILK). Métodos: Ratos Wistar machos e fêmeas foram divididos em 3 grupos: grupo sham, grupo com IM de extensão moderada (tamanho: 20-39% da área do VE); grupo com IM de grande extensão (tamanho: ≥ 40% da área do VE). O IM foi produzido por oclusão coronária e as análises ecocardiográficas foram obtidas após 6 semanas para avaliar a extensão do IM, bem como a morfologia e função do VE. RT-PCR em tempo real e Western blott foram realizados para quantificar a ILK no miocárdio. Resultados: A extensão do IM foi semelhante entre os gêneros. O IM resultou em disfunção sistólica e aumento do tamanho do VE no final da diástole e da sístole em função do tamanho da área necrótica para ambos os sexos. Ratos fêmeas com IM de grande extensão apresentaram dilatação diastólica e sistólica inferior a de ratos machos, mas a disfunção do VE foi semelhante em ambos os sexos. Os níveis gênicos e proteicos de ILK aumentaram em ratos fêmeas com infartos de extensão moderada e grande, mas apenas ratos machos com infartos de grande extensão apresentaram níveis alterados de mRNA do ILK. Uma correlação linear negativa foi observada entre as dimensões do VE e a expressão de ILK em ratos fêmeas com IM de grande extensão. Conclusões: A expressão de ILK pós-IM variou de maneira gênero-especifica, e os níveis mais elevados de ILK observados em fêmeas podem ser suficientes para melhorar a geometria do VE, mas não suficientes para melhorar a função do VE.FAPESPUniversidade Nove de Julho Programa de Pós-graduação em Ciências da ReabilitaçãoUniversidade Federal de São Paulo (UNIFESP) Departamento de CardiologiaUniversidade Federal de São Paulo (UNIFESP) Departamento de PatologiaUNIFESP, Depto. de CardiologiaUNIFESP, Depto. de PatologiaSciEL