Ataxia-telangiectasia mutated kinase (ATM), a serine/threonine kinase, plays a role in DNA damage repair, redox sensing, and metabolism. In the heart, ATM contributes significantly in the myocardial infarction (MI)-induced cardiac remodeling with effects on fibrosis, hypertrophy, apoptosis and inflammation. This study investigates the role of ATM deficiency in 14 weeks Western-type diet (WD)-induced cardiac outcomes prior to and 1-day post-MI in a sex-specific manner using wild-type (WT) and ATM heterozygous knockout (hKO) mice. In male mice, ATM deficiency induced rapid body weight gain and preload-associated dysfunction, while WT mice displayed afterload-associated dysfunction 14 weeks post-WD. Myocyte apoptosis and hypertrophy were higher in hKO-WD versus WT-WD. WD increased fibrosis, and expression of collagen-1α1, MMP-2 and MMP-9 only in WT-WD. AMPK activation was higher, while activation of mTOR and NF-kB was lower in hKO-WD versus hKO-NC. Serum levels of IL-12(p70), eotaxin, IFN-γ, MIP-1α, and MIP-1β were higher in hKO-WD versus WT-WD. Conversely, female hKO-WD mice exhibited an attenuation of weight gain and maintenance of heart function. Cholesterol, triglyceride, and glucose levels were higher in female hKO-WD. WD-induced apoptosis and Bax expression were lower in hKO-WD vs WT-WD. Collagen-1α1 expression was higher in hKO-WD vs WT-WD. MMP-2 and MMP-9 expression increased only in WT-WD. MI decreased cardiac function in both male and female mice versus their WD counterparts. The cardioprotective effects of ATM deficiency in terms of heart function were abolished in female mice 1 day post-MI. MI led to a similar infarct size and increase in apoptosis in the two WD-MI groups of both sexes. These data suggest that – 1) ATM deficiency associates with systolic and preload associated diastolic dysfunction, and exacerbates apoptosis, hypertrophy, and fibrosis in male mice in response to WD; 2) In female mice, ATM deficiency plays a cardioprotective role with preserved systolic function and decreased apoptosis in response to WD; 3) the sex-specific cardioprotective effects of ATM deficiency in females were abolished 1day post-MI. Thus, ATM deficiency affects cardiac structure and function in a sex-specific manner in response to WD and early post-MI.

Ischemic heart disease is a leading cause of death worldwide. Osteopontin (OPN), a cell-secreted extracellular matrix protein, is suggested to play a cardioprotective role in mouse models of ischemic heart disease. The objective of this study was to examine the role of OPN in modulation of systolic and diastolic functional parameters of the heart following mouse ischemia/reperfusion (I/R) injury. For this, wild-type (WT) and OPN-knockout (KO) mice aged approximately 4 months were subjected to cardiac ischemia for 45 minutes by the ligation of the left anterior descending coronary artery (LAD) followed by reperfusion of LAD by snipping the ligature. Heart function was measured using echocardiography at baseline, 1, 3, 7, 14, and 27 days post-I/R injury. M-mode echocardiographic images were used to calculate % fractional shortening [%FS], % ejection fraction [%EF], end-systolic volume [ESV], and end-diastolic volume [EDV], while pulsed wave Doppler images were used to measure aortic ejection time [AET], isovolumic relaxation time [IVRT], and total systolic time [TST]. Velocity of circumferential fiber shortening (Vcf) was calculated using FS and AET. I/R injury significantly decreased %EF and %FS in both WT and KO groups at all time points (1, 3, 7, 14, and 27 days post-I/R) versus the baseline. However, the decrease in % EF and %FS was significantly greater in KO-I/R group versus WT-I/R at 3, 7, 14 and 27 days post-I/R. I/R-mediated increase in ESV and EDV were significantly greater in KO-MI group versus WT-MI 3 day post-I/R. AET was significantly higher in WT-I/R group 27 days post-I/R versus baseline. However, AET was significantly lower in KO-I/R group 3 and 27 days post-I/R versus WT-I/R. IVRT was significantly higher in KO-I/R group 27 days post-I/R vs baseline. However, IVRT was significantly lower in KO-I/R group 1 day post-I/R vs WT-I/R. TST remained unchanged in WT and KO groups post-I/R versus their respective baseline groups. However, TST was significantly lower in KO-I/R group versus WT-I/R at 3 days post-I/R. Vcf was significantly higher at basal levels in the KO versus WT mice. I/R injury decreased Vcf in both groups versus their baseline at all time-points. These data provide evidence that lack of OPN deteriorates systolic and diastolic functional parameters of the heart following I/R injury, suggesting a cardioprotective role of OPN in myocardial remodeling post-IR.

Background: Ataxia-telangiectasia results from mutations in ataxia telangiectasia mutated kinase (ATM) gene. We recently reported that ATM deficiency attenuates left ventricular (LV) dysfunction and dilatation 7 days after myocardial infarction (MI) with increased apoptosis and fibrosis. Here we investigated the role of ATM in the induction of inflammatory response, and activation of survival signaling molecules in the heart acute post-MI. Methods and Results: LV structure, function, inflammatory response, and biochemical parameters were measured in wild-type (WT) and ATM heterozygous knockout (hKO) mice 1 and 3 days post-MI. ATM deficiency had no effect on infarct size. MI-induced decline in heart function, as measured by changes in percent fractional shortening, ejection fraction and LV end systolic and diastolic volumes, was lower in hKO-MI versus WT-MI (n=10 to 12). The number of neutrophils and macrophages was significantly lower in the infarct LV region of hKO versus WT 1 day post-MI. Fibrosis and expression of a-smooth muscle actin (myofibroblast marker) were higher in hKO-MI, while active TGF-β1 levels were higher in the WT-MI 3 days post-MI. Myocyte cross-sectional area was higher in hKO-sham with no difference between the two MI groups. MMP-9 protein levels were similarly increased in the infarct LV region of both MI groups. Apoptosis was significantly higher in the infarct LV region of hKO at both time points. Akt activation was lower, while Bax expression was higher in hKO-MI infarct. Conclusion: ATM deficiency results in decreased dilative remodeling and delays inflammatory response acute post-MI. However, it associates with increased fibrosis and apoptosis.

β-Adrenergic receptor (β-AR) stimulation induces cardiac myocyte apoptosis and plays an important role in myocardial remodeling. Here we investigated expression of various apoptosis-related genes affected by β-AR stimulation, and examined first time the role of ataxia telangiectasia mutated kinase (ATM) in cardiac myocyte apoptosis and myocardial remodeling following β-AR stimulation. cDNA array analysis of 96 apoptosis-related genes indicated that β-AR stimulation increases expression of ATM in the heart. In vitro, RT-PCR confirmed increased ATM expression in adult cardiac myocytes in response to β-AR stimulation. Analysis of left ventricular structural and functional remodeling of the heart in wild-type (WT) and ATM heterozygous knockout mice (hKO) 28 days after ISO-infusion showed increased heart weight to body weight ratio in both groups. M-mode echocardiography showed increased percent fractional shortening (%FS) and ejection fraction (EF%) in both groups 28 days post ISO-infusion. Interestingly, the increase in %FS and EF% was significantly lower in the hKO-ISO group. Cardiac fibrosis and myocyte apoptosis were higher in hKO mice at baseline and ISO-infusion increased fibrosis and apoptosis to a greater extent in hKO-ISO hearts. ISO-infusion increased phosphorylation of p53 (Serine-15) and expression of p53 and Bax to a similar extent in both groups. hKO-Sham and hKO-ISO hearts exhibited reduced intact β1 integrin levels. MMP-2 protein levels were significantly higher, while TIMP-2 protein levels were lower in hKO-ISO hearts. MMP-9 protein levels were increased in WT-ISO, not in hKO hearts. In conclusion, ATM plays a protective role in cardiac remodeling in response to β-AR stimulation.

Ischemic heart disease represents a leading cause of death worldwide. Ischemia denotes an insufficient supply of oxygenated blood to the heart due to occlusion of the coronary vessels. Timely reperfusion, i.e., restoring blood flow to the ischemic part of the heart, limits ischemic damage. However, reperfusion itself induces injury to the heart. This phenomenon is referred as ischemia/reperfusion (I/R) injury. Osteopontin (OPN), also known as cytokine Eta-1, is a cell-secreted extracellular matrix protein. Expression of OPN increases in the heart in response to a variety of pathological conditions. Mice lacking OPN exhibit exaggerated left ventricular dilation in non-reperfused model of myocardial remodeling. Cardioprotective role of OPN has also been demonstrated in a mouse model of repetitive I/R injury for 7 days. The objective of this study was to examine the role of OPN in modulation of systolic and diastolic parameters of the heart following I/R injury in a time-dependent manner. For this study, wild type (WT) and OPN knockout (KO) mice aged ~4 months were subjected to cardiac ischemia by the ligation of left anterior descending coronary artery (LAD). Following 45 min of ischemia, the LAD was reperfused by snipping the ligature. Heart function was measured using echocardiography at baseline, 3, 7, 14, and 27 days following I/R injury. M-mode echocardiographic images were used to calculate the systolic parameters (% fractional shortening [%FS], % ejection fraction [%EF], and end-systolic volume [ESV]), while pulse wave Doppler images were used to calculate diastolic parameter (aortic ejection time; [AET]). Global cardiac function was evaluated using myocardial performance index (MPI; a Doppler-derived index which combines systolic and diastolic functions). At basal levels, most of the systolic and diastolic parameters remained unchanged between the two groups. I/R injury decreased %FS and EF in both groups vs the baseline values at 3, 7, 14 and 27 days post-I/R. However, the decrease in %FS and EF was significantly greater in KO-I/R vs WT-I/R group. ESV was significantly higher in WT mice 7 days post-I/R, and stayed higher 14 and 27 days post-I/R vs baseline. However, the increase in ESV was significantly greater in KO mice 3 day post-I/R, and remained higher vs WT-I/R during the time course. AET was lower in WT group 14 days post-I/R vs baseline. On the other hand, AET was significantly lower in KO group 3, 7, 14 and 27 days post-I/R vs WT-I/R. MPI was higher in WT group 7 days post-IR vs baseline. MPI decreased significantly in WT group 27 days vs 7 days post-I/R. In KO group, MPI was significantly higher than WT mice at baseline, and remained higher 3 and 27 day post-I/R vs WT-I/R. Thus, lack of OPN decreases systolic and diastolic functional parameters of the heart following I/R injury, suggesting a cardioprotective role of OPN in myocardial remodeling post-IR.

No description available.

No description available.

INTRODUÇÃO: A hipertensão pulmonar (HP) é comorbidade frequente em pacientes com insuficiência cardíaca (IC) e está associada ao pior prognóstico no pós-transplante cardíaco (TC). O teste de reatividade pulmonar realizado no préoperatório de TC avalia a reversibilidade da HP aos vasodilatadores, uma vez que a HP reversível tem melhor prognóstico. O nitroprussiato de sódio (NPS) é o vasodilatador mais utilizado, porém é associado a elevados índices de hipotensão arterial sistêmica, disfunção ventricular do enxerto transplantado e elevadas taxas de desqualificação para o TC. O sildenafil (SIL) é um inibidor seletivo da fosfodiesterase tipo 5 e utilizado no tratamento da HP idiopática, sem promover efeitos sistêmicos negativos. Neste estudo, objetivou-se avaliar os efeitos hemodinâmicos agudos do SIL e NPS sobre a HP de candidatos ao TC e seus efeitos sobre o remodelamento cardíaco reverso, definido como redução dos diâmetros ventriculares e melhora da função cardíaca, por meio da análise ecocardiográfica, hemodinâmica e bioquímica. MÉTODOS: Os pacientes foram submetidos, simultaneamente, ao cateterismo cardíaco direito para medida das pressões pulmonares, ao ecocardiograma, à dosagem sanguínea de BNP e à gasometria venosa, prosseguindo no estudo caso preenchessem os critérios de inclusão previamente estabelecidos. Os pacientes selecionados foram randomizados a receber NPS (1 - 2 ?g/Kg/min) ou SIL (100mg, dose única, via oral) e, após o período de tempo predeterminado, procedeu-se à nova avaliação hemodinâmica, ecocardiográfica e bioquímica. RESULTADOS: NPS e SIL reduziram significativamente a pressão sistólica da artéria pulmonar (NPS: 64,7 vs. 57mmHg, p = 0,002; SIL: 61,07 vs. 50mmHg, p < 0,001), porém o grupo que recebeu NPS apresentou redução acentuada da média da pressão arterial sistêmica (85,2 vs. 69,8mmHg, p < 0,001). Do ponto de vista ecocardiográfico, ambas as medicações promoveram redução da área ventricular direita (NPS: 29,2 vs. 25,7mm, p = 0,003; SIL: 29,4 vs. 23,8mm, p < 0,001) e elevação da fração de ejeção ventricular esquerda (NPS: 23,5 vs. 24,8 %, p = 0,02; SIL: 23,8 vs. 26 %, p < 0,001). Por outro lado, o grupo que recebeu SIL, ao contrário do NPS, apresentou melhora no índice de saturação venosa de oxigênio, medido pela gasometria venosa (SIL: 49,2 vs. 58,9%, p < 0,001). Os vasodilatadores não interferiram de forma significativa nos níveis séricos de BNP. CONCLUSÃO: Sildenafil e nitroprussiato de sódio reduziram significativamente a hipertensão pulmonar de pacientes com IC avançada. Ambos estiveram associados ao remodelamento cardíaco reverso, com diminuição da área ventricular direita e melhora da função cardíaca, medidos por parâmetros hemodinâmicos, ecocardiográficos e bioquímicos. O NPS, ao contrário do SIL, esteve associado à significativa hipotensão arterial sistêmica e piora do índice de saturação venosa de oxigênio. / INTRODUCTION: Pulmonary hypertension (PH) is a common comorbidity in heart failure (HF) patients and is associated with poor post heart transplant (HT) prognosis. The pulmonary reactivity test performed pre-operatively to the HT evaluates the reversibility of the PH to the vasodilators, since a reversible PH has a better prognosis. Sodium nitroprusside (SNP) is the most widely used vasodilator, but is associated with higher rates of systemic arterial hypotension, ventricular dysfunction of the transplanted graft and higher rejection rates of the HT. Sildenafil (SIL) is a selective phosphodiesterase type 5 inhibitor and is used in the treatment of idiopathic PH, without producing negative systemic effects. This study aimed to evaluate the acute hemodynamic effects of SIL and SNP on the PH of HT candidates and their effects on reverse cardiac remodeling, defined as a reduction in ventricular diameter and improvement of cardiac function, through echocardiographic, hemodynamic and biochemical analysis. METHODS: The patients simultaneously underwent: right cardiac catheterization, to measure the pulmonary pressure, echocardiogram and blood dosage of BNP and venous gas analysis, continuing in the study if the previously established inclusion criteria were met. The selected patients were randomly given SNP (1 - 2 ?g/Kg/min) or SIL (100mg, single dose, orally) and after a predetermined period of time went for a new hemodynamic, echocardiographic and biochemical evaluation. RESULTS: SNP and SIL significantly reduced the systolic pulmonary artery pressure (SNP: 64.7 vs. 57mmHg, p = 0.002; SIL 61.07 vs. 50mmHg, p = 0.001). However the group which received SNP showed a marked reduction in mean systemic blood pressure (85.2 vs. 69.8mmHg, p < 0.001). From the point of view of the echocardiography, both the medications produced a reduction in right ventricular size (SNP: 29.2 vs. 25.7mm, p = 0.003; SIL 29.4 vs. 23.8mm, p < 0.001) and an increase of the left ventricular ejection fraction (NPS: 23.5 vs. 24.8 %, p = 0.02; SIL: 23.8 vs. 26 %, p < 0.001). On the other hand, the group which received SIL, unlike the SNP, showed improvements in the rate of oxygen venous saturation, measured by venous gas analysis (SIL: 49.2 vs. 58.9%, p < 0.001). Neither group significantly affected the serum levels of BNP. CONCLUSION: Sildenafil and sodium nitroprusside significantly reduced pulmonary hypertension in patients with advanced HF. Both were associated with reverse cardiac remodeling, with a reduction in right ventricular area and improvement of the cardiac function, measured by hemodynamic, echocardiographic and biochemical parameters. SNP, unlike SIL, was associated to significant systemic arterial hypotension and worsening of the rate of venous oxygen saturation.

O presente trabalho buscou identificar uma possível relação causa-efeito entre exercício, SRA, remodelamento cardíaco e função autonômica na redução da pressão arterial (PA) induzida pelo treinamento aeróbio (T) iniciado na fase pré-hipertensiva. SHR, com 4 semanas de idade, foram submetidos ao T (55% da capacidade física, 1h/dia, 5x/semana) ou mantidos sedentários (S) por 8 semanas. WKY serviram como controle temporal. Os parâmetros foram avaliados nas semanas 0, 1, 2, 4 e 8. Nossos dados indicam que o treinamento iniciado ainda na fase pré-hipertensiva, protege o coração reduzindo a expressão relativa de receptores AT1 e a hipertrofia cardíaca, reduz a FC basal e aumenta sua variabilidade por facilitar o componente vagal alterando o balanço simpato-vagal ao coração. Estas adaptações contribuem para retardar a instalação, reduzindo substancialmente os níveis pressóricos atingidos na fase crônica da hipertensão arterial. A oposição precoce aos efeitos deletérios da hipertensão pelo treinamento é fundamental para minimizar seus prejuízos estruturais e funcionais. / In the present dissertation, we identified a possible cause-effect relation between exercise training, SRA, cardiac remodeling and autonomic function during the establishment of essential hypertension. 4 weeks-old SHR were submitted to aerobic training (5x/week; 1hour/day; 55% of maximal exercise capacity). Factors were assessed on weeks 0,1,2,4 and 8. Exercise training was able to attenuate increase AP, vascular sympathetic activity, cardiac remodeling and cardiac AT1 protein expression; to intensify decrease HR; to increase HR variance and cardiac vagal activity. Our data indicate that aerobic training, during pre-hypertensive phases, attenuates cardiac remodeling associated with decrease of AP, cardiac AT1 protein expression and autonomic dysfunction in SHR. Premature modulation of maladaptative effects of hypertension induced by aerobic tranining seem to be crucial to minimize long-term deleterious effects in cardiac structure and function.

A hipertensão arterial é acompanhada de hiperatividade do sistema renina angiotensina (SRA). Demonstramos em ratos SHR que a hiperativação do SRA plasmático antecede o cardíaco. A hiperatividade do SRA foi acompanhada de aumento do estresse oxidativo, perfil inflamatório, hipertrofia cardíaca e deposição de colágeno no ventrículo esquerdo (VE) de SHR. O treinamento aeróbio de baixa a moderada promoveu pronta redução do SRA cardíaco e plasmático seguido por normalização do estresse oxidativo e redução da inflamação no VE. Embora não houve alteração na hipertrofia cardíaca, observamos redução da deposição de colágeno no VE de SHR treinados. Sugerimos que a redução do SRA foi determinante na modulação dos parâmetros analisados contribuindo para a manutenção das estruturas cardíacas e evitando remodelamento cardíaco deletério nos SHR treinados. / The hypertension is followed by renin angiotensin system hyperactivity (RAS). We have showed in SHR rats that plasma RAS hyperactivity precedes the cardiac RAS hyperactivity. Furthermore the RAS hyperactivity was followed by oxidative stress and inflammation increase as well as left ventricle (LV) collagen deposition in SHR. The aerobic training promoted prompt cardiac and plasma RAS activity reduction. It was followed by oxidative stress normalization and inflammatory reduction. Although we did not observe cardiac hypertrophy change, the collagen deposition was reduced in SHR trained group. We suggest the RAS activity reduction as a determinant condition to the beneficial adaptations occurred in the parameters analyzed. Thus contributing to maintenance of cardiac structures and avoids the deleterious cardiac remodeling in SHR.