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1.
J Mol Cell Cardiol ; 131: 53-65, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31005484

RESUMO

AIMS: Atrial contractile dysfunction is associated with increased mortality in heart failure (HF). We have shown previously that a metabolic syndrome-based model of HFpEF and a model of hypertensive heart disease (HHD) have impaired left atrial (LA) function in vivo (rat). In this study we postulate, that left atrial cardiomyocyte (CM) and cardiac fibroblast (CF) paracrine interaction related to the inositol 1,4,5-trisphosphate signalling cascade is pivotal for the manifestation of atrial mechanical dysfunction in HF and that quantitative atrial remodeling is highly disease-dependent. METHODS AND RESULTS: Differential remodeling was observed in HHD and HFpEF as indicated by an increase of atrial size in vivo (HFpEF), unchanged fibrosis (HHD and HFpEF) and a decrease of CM size (HHD). Baseline contractile performance of rat CM in vitro was enhanced in HFpEF. Upon treatment with conditioned medium from their respective stretched CF (CM-SF), CM (at 21 weeks) of WT showed increased Ca2+ transient (CaT) amplitudes related to the paracrine activity of the inotrope endothelin (ET-1) and inositol 1,4,5-trisphosphate induced Ca2+ release. Concentration of ET-1 was increased in CM-SF and atrial tissue from WT as compared to HHD and HFpEF. In HHD, CM-SF had no relevant effect on CaT kinetics. However, in HFpEF, CM-SF increased diastolic Ca2+ and slowed Ca2+ removal, potentially contributing to an in-vivo decompensation. During disease progression (i.e. at 27 weeks), HFpEF displayed dysfunctional excitation-contraction-coupling (ECC) due to lower sarcoplasmic-reticulum Ca2+ content unrelated to CF-CM interaction or ET-1, but associated with enhanced nuclear [Ca2+]. In human patients, tissue ET-1 was not related to the presence of arterial hypertension or obesity. CONCLUSIONS: Atrial remodeling is a complex entity that is highly disease and stage dependent. The activity of fibrosis related to paracrine interaction (e.g. ET-1) might contribute to in vitro and in vivo atrial dysfunction. However, during later stages of disease, ECC is impaired unrelated to CF.

2.
Sci Rep ; 8(1): 17772, 2018 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-30538258

RESUMO

Given the association between high aerobic capacity and the prevention of metabolic diseases, elucidating the mechanisms by which high aerobic capacity regulates whole-body metabolic homeostasis is a major research challenge. Oxidative post-translational modifications (Ox-PTMs) of proteins can regulate cellular homeostasis in skeletal and cardiac muscles, but the relationship between Ox-PTMs and intrinsic components of oxidative energy metabolism is still unclear. Here, we evaluated the Ox-PTM profile in cardiac and skeletal muscles of rats bred for low (LCR) and high (HCR) intrinsic aerobic capacity. Redox proteomics screening revealed different cysteine (Cys) Ox-PTM profile between HCR and LCR rats. HCR showed a higher number of oxidized Cys residues in skeletal muscle compared to LCR, while the opposite was observed in the heart. Most proteins with differentially oxidized Cys residues in the skeletal muscle are important regulators of oxidative metabolism. The most oxidized protein in the skeletal muscle of HCR rats was malate dehydrogenase (MDH1). HCR showed higher MDH1 activity compared to LCR in skeletal, but not cardiac muscle. These novel findings indicate a clear association between Cys Ox-PTMs and aerobic capacity, leading to novel insights into the role of Ox-PTMs as an essential signal to maintain metabolic homeostasis.

3.
Int J Cardiol ; 272: 194-201, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30173922

RESUMO

BACKGROUND: Disruption of endoplasmic reticulum (ER) homeostasis is a common feature of cardiac diseases. However, the signaling events involved in ER stress-induced cardiac dysfunction are still elusive. Here, we uncovered a mechanism by which disruption of ER homeostasis impairs cardiac contractility. METHODS/RESULTS: We found that ER stress is associated with activation of JNK and upregulation of BNIP3 in a post-myocardial infarction (MI) model of cardiac dysfunction. Of interest, 4-week treatment of MI rats with the chemical ER chaperone 4-phenylbutyrate (4PBA) prevented both activation of JNK and upregulation of BNIP3, and improved cardiac contractility. We showed that disruption of ER homeostasis by treating adult rat cardiomyocytes in culture with tunicamycin leads to contractile dysfunction through JNK signaling pathway. Upon ER stress JNK upregulates BNIP3 in a FOXO3a-dependent manner. Further supporting a BNIP3 mechanism for ER stress-induced deterioration of cardiac function, siRNA-mediated BNIP3 knockdown mitigated ER stress-induced cardiomyocyte dysfunction by reestablishing sarcoplasmic reticulum Ca2+ content. CONCLUSIONS: Collectively, our data identify JNK-dependent upregulation of BNIP3 as a critical process involved in ER stress-induced cardiomyocyte contractile dysfunction and highlight 4PBA as a potential intervention to counteract ER stress-mediated BNIP3 upregulation in failing hearts.

4.
Int J Cardiol ; 273: 147-154, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30193792

RESUMO

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction, but the molecular mechanisms still remain unclear. Whether exercise training (ET) along with which optimal modality can improve endothelial function is controversial. The present study used a hypertensive, diabetic-driven HFpEF animal model (ZSF1 rats) to determine whether different training modalities (moderate-continuous (MCT) and high-intensity interval training (HIIT)) could reverse endothelial dysfunction and to understand the underlying molecular mechanisms. METHODS AND RESULTS: The development of HFpEF in ZSF1 obese animals was confirmed by echocardiography and hemodynamic measurements. Thereafter, animals were randomized into following groups: 1) sedentary, 2) 8 weeks of MCT, 3) 8 weeks of HIIT. ZSF1 lean animals served as control. In vitro measurement of endothelial function in aortic rings revealed significantly impaired endothelial-dependent and -independent vasodilation in HFpEF, which was reversed by MCT and HIIT. At the molecular level, the development of endothelial dysfunction was associated with a reduced expression / activation of endothelial nitric oxide synthase (eNOS), an increase in NADPH and activation of c-Jun N-terminal protein kinase (JNK), a reduced collagen I/III ratio and a reduced lining of the vessel wall by endothelial cells. ET primarily decreased NADPH oxidase expression, and JNK activation, elevated collagen I/III ratio while further improving aortic endothelial cell coverage. CONCLUSIONS: The present study provides evidence that endothelial dysfunction occurs in experimental HFpEF and that ET, independent of the studied training modality, reverses endothelial dysfunction and specific molecular alterations. ET may therefore provide an important therapeutic intervention for HFpEF patients.

5.
J Card Fail ; 24(9): 603-613, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30195827

RESUMO

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is underpinned by detrimental skeletal muscle alterations that contribute to disease severity, yet underlying mechanisms and therapeutic treatments remain poorly established. This study used a nonhuman animal model of HFpEF to better understand whether skeletal muscle abnormalities were (1) fiber-type specific and (2) reversible by various exercise training regimes. METHODS AND RESULTS: Lean control rats were compared with obese ZSF1 rats at 20 weeks and then 8 weeks after sedentary, high-intensity interval training, or moderate continuous treadmill exercise. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were assessed for fiber size, capillarity, glycolytic metabolism, autophagy, and contractile function. HFpEF reduced fiber size and capillarity by 20%-50% (P < .05) in both soleus and EDL, but these effects were not reversed by endurance training. In contrast, both endurance training regimes in HFpEF attenuated the elevated lactate dehydrogenase activity observed in the soleus. Autophagy was down-regulated in EDL and up-regulated in soleus (P < .05), with no influence of endurance training. HFpEF impaired contractile forces of both muscles by ∼20% (P < .05), and these were not reversed by training. CONCLUSIONS: Obesity-related HFpEF was associated with detrimental structural, cellular, and functional alterations to both slow-oxidative and fast-glycolytic skeletal muscles that could not be reversed by endurance training.

6.
Front Physiol ; 9: 206, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29593565

RESUMO

Aims: Increasing age is the most important risk factor for atrial fibrillation (AF). Very high doses of exercise training might increase AF risk, while moderate levels seem to be protective. This study aimed to examine the effects of age on vulnerability to AF and whether long-term aerobic interval training (AIT) could modify these effects. Methods: Nine months old, male Sprague-Dawley rats were randomized to AIT for 16 weeks (old-ex) or to a sedentary control group (old-sed), and compared to young sedentary males (young-sed). After the intervention, animals underwent echocardiography, testing of exercise capacity (VO2max), and electrophysiology with AF induction before ex vivo electrophysiology. Fibrosis quantification, immunohistochemistry and western blotting of atrial tissue were performed. Results: Sustained AF was induced in vivo in 4 of 11 old-sed animals, but none of the old-ex or young-sed rats (p = 0.006). VO2max was lower in old-sed, while old-ex had comparable results to young-sed. Fibrosis was increased in old-sed (p = 0.006), with similar results in old-ex. There was a significantly slower atrial conduction in old-sed (p = 0.038), with an increase in old-ex (p = 0.027). Action potential duration was unaltered in old-sed, but prolonged in old-ex (p = 0.036). There were no differences in amount of atrial connexin 43 between groups, but a lateralization in atrial cardiomyocytes of old-sed, with similar findings in old-ex. Conclusion: AF vulnerability was higher in old-sed animals, associated with increased atrial fibrosis, lateralization of connexin-43, and reduced atrial conduction velocity. AIT reduced the age-associated susceptibility to AF, possibly through increased conduction velocity and prolongation of action potentials.

7.
J Am Heart Assoc ; 6(10)2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-29066440

RESUMO

BACKGROUND: Respiratory muscle weakness contributes to exercise intolerance in patients with heart failure with a preserved ejection fraction (HFpEF)-a condition characterized by multiple comorbidities with few proven treatments. We aimed, therefore, to provide novel insight into the underlying diaphragmatic alterations that occur in HFpEF by using an obese cardiometabolic rat model and further assessed whether exercise training performed only after the development of overt HFpEF could reverse impairments. METHODS AND RESULTS: Obese ZSF1 rats (n=12) were compared with their lean controls (n=8) at 20 weeks, with 3 additional groups of obese ZSF1 rats compared at 28 weeks following 8 weeks of either sedentary behavior (n=13), high-intensity interval training (n=11), or moderate-continuous training (n=11). Obese rats developed an obvious HFpEF phenotype at 20 and 28 weeks. In the diaphragm at 20 weeks, HFpEF induced a shift towards an oxidative phenotype and a fiber hypertrophy paralleled by a lower protein expression in MuRF1 and MuRF2, yet mitochondrial and contractile functional impairments were observed. At 28 weeks, neither the exercise training regimen of high-intensity interval training or moderate-continuous training reversed any of the diaphragm alterations induced by HFpEF. CONCLUSIONS: This study, using a well-characterized rat model of HFpEF underpinned by multiple comorbidities and exercise intolerance (ie, one that closely resembles the patient phenotype), provides evidence that diaphragm alterations and dysfunction induced in overt HFpEF are not reversed following 8 weeks of aerobic exercise training. As such, whether alternative therapeutic interventions are required to treat respiratory muscle weakness in HFpEF warrants further investigation.


Assuntos
Diafragma/fisiopatologia , Tolerância ao Exercício , Insuficiência Cardíaca/terapia , Treinamento Intervalado de Alta Intensidade , Debilidade Muscular , Obesidade/terapia , Volume Sistólico , Função Ventricular Esquerda , Animais , Diafragma/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Oxirredução , Fenótipo , Ratos Zucker , Fatores de Tempo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
8.
Circ Heart Fail ; 9(9)2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27609832

RESUMO

BACKGROUND: A greater understanding of the different underlying mechanisms between patients with heart failure with reduced (HFrEF) and with preserved (HFpEF) ejection fraction is urgently needed to better direct future treatment. However, although skeletal muscle impairments, potentially mediated by inflammatory cytokines, are common in both HFrEF and HFpEF, the underlying cellular and molecular alterations that exist between groups are yet to be systematically evaluated. The present study, therefore, used established animal models to compare whether alterations in skeletal muscle (limb and respiratory) were different between HFrEF and HFpEF, while further characterizing inflammatory cytokines. METHODS AND RESULTS: Rats were assigned to (1) HFrEF (ligation of the left coronary artery; n=8); (2) HFpEF (high-salt diet; n=10); (3) control (con: no intervention; n=7). Heart failure was confirmed by echocardiography and invasive measures. Soleus tissue in HFrEF, but not in HFpEF, showed a significant increase in markers of (1) muscle atrophy (ie, MuRF1, calpain, and ubiquitin proteasome); (2) oxidative stress (ie, higher nicotinamide adenine dinucleotide phosphate oxidase but lower antioxidative enzyme activities); (3) mitochondrial impairments (ie, a lower succinate dehydrogenase/lactate dehydrogenase ratio and peroxisome proliferator-activated receptor-γ coactivator-1α expression). The diaphragm remained largely unaffected between groups. Plasma concentrations of circulating cytokines were significantly increased in HFrEF for tumor necrosis factor-α, whereas interleukin-1ß and interleukin-12 were higher in HFpEF. CONCLUSIONS: Our findings suggest, for the first time, that skeletal muscle alterations are exacerbated in HFrEF compared with HFpEF, which predominantly reside in limb, rather than in respiratory, muscle. This disparity may be mediated, in part, by the different circulating inflammatory cytokines that were elevated between HFpEF and HFrEF.


Assuntos
Citocinas/sangue , Insuficiência Cardíaca/sangue , Mediadores da Inflamação/sangue , Músculo Esquelético/metabolismo , Volume Sistólico , Função Ventricular Esquerda , Animais , Diafragma/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Interleucina-12/sangue , Interleucina-1beta/sangue , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Atrofia Muscular/sangue , Atrofia Muscular/patologia , Estresse Oxidativo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/sangue , Regulação para Cima
9.
J Cell Mol Med ; 20(11): 2208-2212, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27305869

RESUMO

Cardiac endoplasmic reticulum (ER) stress through accumulation of misfolded proteins plays a pivotal role in cardiovascular diseases. In an attempt to reestablish ER homoeostasis, the unfolded protein response (UPR) is activated. However, if ER stress persists, sustained UPR activation leads to apoptosis. There is no available therapy for ER stress relief. Considering that aerobic exercise training (AET) attenuates oxidative stress, mitochondrial dysfunction and calcium imbalance, it may be a potential strategy to reestablish cardiac ER homoeostasis. We test the hypothesis that AET would attenuate impaired cardiac ER stress after myocardial infarction (MI). Wistar rats underwent to either MI or sham surgeries. Four weeks later, rats underwent to 8 weeks of moderate-intensity AET. Myocardial infarction rats displayed cardiac dysfunction and lung oedema, suggesting heart failure. Cardiac dysfunction in MI rats was paralleled by increased protein levels of UPR markers (GRP78, DERLIN-1 and CHOP), accumulation of misfolded and polyubiquitinated proteins, and reduced chymotrypsin-like proteasome activity. These results suggest an impaired cardiac protein quality control. Aerobic exercise training improved exercise capacity and cardiac function of MI animals. Interestingly, AET blunted MI-induced ER stress by reducing protein levels of UPR markers, and accumulation of both misfolded and polyubiquinated proteins, which was associated with restored proteasome activity. Taken together, our study provide evidence for AET attenuation of ER stress through the reestablishment of cardiac protein quality control, which contributes to better cardiac function in post-MI heart failure rats. These results reinforce the importance of AET as primary non-pharmacological therapy to cardiovascular disease.


Assuntos
Estresse do Retículo Endoplasmático , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Condicionamento Físico Animal , Proteínas/metabolismo , Animais , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca , Infarto do Miocárdio/complicações , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Dobramento de Proteína , Ratos Wistar
10.
J Appl Physiol (1985) ; 119(6): 745-52, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26229002

RESUMO

Heart failure patients with preserved left ventricular ejection fraction (HFpEF) have endothelial dysfunction, but the underlying molecular mechanisms remain unknown. In addition, whether exercise training improves endothelial function in HFpEF is still controversial. The present study therefore aimed to determine the functional and molecular alterations in the endothelium associated with HFpEF, while further assessing the effects of high-intensity interval training (HIT). Female Dahl salt-sensitive rats were randomized for 28 wk into the following groups: 1) control: fed 0.3% NaCl; 2) HFpEF: fed 8% NaCl; and 3) HFpEF + HIT: animals fed 8% NaCl and HIT treadmill exercise. Echocardiography and invasive hemodynamic measurements were used to assess diastolic dysfunction. Endothelial function of the aorta was measured in vitro. Expression of endothelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate-oxidase [NAD(P)H oxidase], and advanced glycation end product (AGE)-modified proteins were quantified by Western blot, and zymography quantified matrix metalloproteinase (MMP) activity. In this model of HFpEF, endothelium-dependent and -independent vasodilation was impaired. However, this was prevented by HIT. In HFpEF protein expression of eNOS was reduced by 47%, but MMP-2 and MMP-9 activity was elevated by 186 and 68%. The expression of AGE-modified proteins was increased by 106%. All of these changes were prevented by HIT. Endothelial function was impaired in this model of HFpEF, which was associated with reduced expression of eNOS, increased MMP activity, and increased AGE-modified proteins. HIT was able to attenuate both these functional and molecular alterations. These findings therefore suggest HFpEF induces endothelial dysfunction, but this is reversible by HIT.


Assuntos
Endotélio/fisiopatologia , Tolerância ao Exercício/fisiologia , Insuficiência Cardíaca/fisiopatologia , Condicionamento Físico Animal/fisiologia , Cloreto de Sódio/metabolismo , Doenças Vasculares/fisiopatologia , Animais , Endotélio/metabolismo , Teste de Esforço/métodos , Feminino , Insuficiência Cardíaca/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Endogâmicos Dahl , Doenças Vasculares/metabolismo , Vasodilatação/fisiologia
11.
Basic Res Cardiol ; 110(4): 44, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26112154

RESUMO

Diabetes mellitus (DM) increases the risk of heart failure after myocardial infarction (MI), and aggravates ventricular arrhythmias in heart failure patients. Although exercise training improves cardiac function in heart failure, it is still unclear how it benefits the diabetic heart after MI. To study the effects of aerobic interval training on cardiac function, susceptibility to inducible ventricular arrhythmias and cardiomyocyte calcium handling in DM mice after MI (DM-MI). Male type 2 DM mice (C57BLKS/J Lepr (db) /Lepr (db) ) underwent MI or sham surgery. One group of DM-MI mice was submitted to aerobic interval training running sessions during 6 weeks. Cardiac function and structure were assessed by echocardiography and magnetic resonance imaging, respectively. Ventricular arrhythmias were induced by high-frequency cardiac pacing in vivo. Protein expression was measured by Western blot. DM-MI mice displayed increased susceptibility for inducible ventricular arrhythmias and impaired diastolic function when compared to wild type-MI, which was associated with disruption of cardiomyocyte calcium handling and increased calcium leak from the sarcoplasmic reticulum. High-intensity exercise recovered cardiomyocyte function in vitro, reduced sarcoplasmic reticulum diastolic calcium leak and significantly reduced the incidence of inducible ventricular arrhythmias in vivo in DM-MI mice. Exercise training also normalized the expression profile of key proteins involved in cardiomyocyte calcium handling, suggesting a potential molecular mechanism for the benefits of exercise in DM-MI mice. High-intensity aerobic exercise training recovers cardiomyocyte function and reduces inducible ventricular arrhythmias in infarcted diabetic mice.


Assuntos
Arritmias Cardíacas/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Infarto do Miocárdio/complicações , Condicionamento Físico Animal , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/fisiologia , Função Ventricular Esquerda
12.
Eur J Heart Fail ; 17(3): 263-72, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25655080

RESUMO

AIMS: Peripheral muscle dysfunction is a key mechanism contributing to exercise intolerance (i.e. breathlessness and fatigue) in heart failure patients with preserved ejection fraction (HFpEF); however, the underlying molecular and cellular mechanisms remain unknown. We therefore used an animal model to elucidate potential molecular, mitochondrial, histological, and functional alterations induced by HFpEF in the diaphragm and soleus, while also determining the possible benefits associated with exercise training. METHODS AND RESULTS: Female Dahl salt-sensitive rats were fed a low (CON; n = 10) or high salt (HFpEF; n = 11) diet of 0.3% or 8% NaCl, respectively, or a high salt diet in combination with treadmill exercise training (n = 11). Compared with low-salt rats, high-salt rats developed (P < 0.05) HFpEF. Compared with CON, the diaphragm of HFpEF rats demonstrated (P < 0.05): a fibre type shift from fast-to-slow twitch; fibre atrophy; a decreased pro-oxidative but increased anti-oxidant capacity; reduced proteasome activation; impaired in situ mitochondrial respiration; and in vitro muscle weakness and increased fatigability. The soleus also demonstrated numerous alterations (P < 0.05), including fibre atrophy, decreased anti-oxidant capacity, reduced mitochondrial density, and increased fatigability. Exercise training, however, prevented mitochondrial and functional impairments in both the diaphragm and soleus (P < 0.05). CONCLUSION: Our findings are the first to demonstrate that HFpEF induces significant molecular, mitochondrial, histological, and functional alterations in the diaphragm and soleus, which were attenuated by exercise training. These data therefore reveal novel mechanisms and potential therapeutic treatments of exercise intolerance in HFpEF.


Assuntos
Diafragma/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/fisiopatologia , Volume Sistólico/fisiologia , Animais , Catalase/metabolismo , Diafragma/metabolismo , Tolerância ao Exercício/fisiologia , Feminino , Insuficiência Cardíaca/metabolismo , Modelos Animais , Músculo Esquelético/metabolismo , Cadeias Leves de Miosina/metabolismo , NADPH Oxidases/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Ratos Endogâmicos Dahl , Superóxido Dismutase/metabolismo , Troponina C/metabolismo
13.
PLoS One ; 8(10): e76568, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24146891

RESUMO

BACKGROUND: Although high aerobic capacity is associated with effective cardiac function, the effect of aerobic capacity on atrial function, especially in terms of cellular mechanisms, is not known. We aimed to investigate whether rats with low inborn maximal oxygen uptake (VO2 max) had impaired atrial myocyte contractile function when compared to rats with high inborn VO2 max. METHODS AND RESULTS: Atrial myocyte function was depressed in Low Capacity Runners (LCR) relative to High Capacity Runners (HCR) which was associated with impaired Ca(2+) handling. Fractional shortening was 52% lower at 2 Hz and 60% lower at 5 Hz stimulation while time to 50% relengthening was 43% prolonged and 55% prolonged, respectively. Differences in Ca(2+) amplitude and diastolic Ca(2+) level were observed at 5 Hz stimulation where Ca(2+) amplitude was 70% lower and diastolic Ca(2+) level was 11% higher in LCR rats. Prolonged time to 50% Ca(2+) decay was associated with reduced sarcoplasmic reticulum (SR) Ca(2+) ATPase function in LCR (39%). Na(+)/Ca(2+) exchanger activity was comparable between the groups. Diastolic SR Ca(2+) leak was increased by 109%. This could be partly explained by increased ryanodine receptors phosphorylation at the Ca(2+)-calmodulin-dependent protein kinase-II specific Ser-2814 site in LCR rats. T-tubules were present in 68% of HCR cells whereas only 33% LCR cells had these structures. In HCR, the significantly higher numbers of cells with T-tubules were combined with greater numbers of myocytes where Ca(2+) release in the cell occurred simultaneously in central and peripheral regions, giving rise to faster and more spatial homogenous Ca(2+)-signal onset. CONCLUSION: This data demonstrates that contrasting for low or high aerobic capacity leads to diverse functional and structural remodelling of atrial myocytes, with impaired contractile function in LCR compared to HCR rats.


Assuntos
Sinalização do Cálcio , Átrios do Coração/citologia , Miócitos Cardíacos/fisiologia , Aerobiose , Animais , Separação Celular , Diástole , Contração Miocárdica/fisiologia , Consumo de Oxigênio/fisiologia , Condicionamento Físico Animal , Ratos , Sarcolema/metabolismo , Retículo Sarcoplasmático/metabolismo
14.
PLoS One ; 8(5): e62452, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23658728

RESUMO

The use of ß-blockers is mandatory for counteracting heart failure (HF)-induced chronic sympathetic hyperactivity, cardiac dysfunction and remodeling. Importantly, aerobic exercise training, an efficient nonpharmacological therapy to HF, also counteracts sympathetic hyperactivity in HF and improves exercise tolerance and cardiac contractility; the latter associated with changes in cardiac Ca(2+) handling. This study was undertaken to test whether combined ß-blocker and aerobic exercise training would integrate the beneficial effects of isolated therapies on cardiac structure, contractility and cardiomyocyte Ca(2+) handling in a genetic model of sympathetic hyperactivity-induced HF (α2A/α2C- adrenergic receptor knockout mice, KO). We used a cohort of 5-7 mo male wild-type (WT) and congenic mice (KO) with C57Bl6/J genetic background randomly assigned into 5 groups: control (WT), saline-treated KO (KOS), exercise trained KO (KOT), carvedilol-treated KO (KOC) and, combined carvedilol-treated and exercise-trained KO (KOCT). Isolated and combined therapies reduced mortality compared with KOS mice. Both KOT and KOCT groups had increased exercise tolerance, while groups receiving carvedilol had increased left ventricular fractional shortening and reduced cardiac collagen volume fraction compared with KOS group. Cellular data confirmed that cardiomyocytes from KOS mice displayed abnormal Ca(2+) handling. KOT group had increased intracellular peak of Ca(2+) transient and reduced diastolic Ca(2+) decay compared with KOS group, while KOC had increased Ca(2+) decay compared with KOS group. Notably, combined therapies re-established cardiomyocyte Ca(2+) transient paralleled by increased SERCA2 expression and SERCA2:PLN ratio toward WT levels. Aerobic exercise trained increased the phosphorylation of PLN at Ser(16) and Thr(17) residues in both KOT and KOCT groups, but carvedilol treatment reduced lipid peroxidation in KOC and KOCT groups compared with KOS group. The present findings provide evidence that the combination of carvedilol and aerobic exercise training therapies lead to a better integrative outcome than carvedilol or exercise training used in isolation.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Carbazóis/farmacologia , Terapia por Exercício , Insuficiência Cardíaca/terapia , Contração Miocárdica , Propanolaminas/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Pressão Sanguínea , Sinalização do Cálcio , Carbazóis/uso terapêutico , Carvedilol , Células Cultivadas , Terapia Combinada , Avaliação Pré-Clínica de Medicamentos , Tolerância ao Exercício , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca , Peroxidação de Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Condicionamento Físico Animal , Propanolaminas/uso terapêutico , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Remodelação Ventricular
15.
IEEE Trans Med Imaging ; 32(7): 1265-76, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23549887

RESUMO

Coherent plane wave compounding is a promising technique for achieving very high frame rate imaging without compromising image quality or penetration. However, this approach relies on the hypothesis that the imaged object is not moving during the compounded scan sequence, which is not the case in cardiovascular imaging. This work investigates the effect of tissue motion on retrospective transmit focusing in coherent compounded plane wave imaging (PWI). Two compound scan sequences were studied based on a linear and alternating sequence of tilted plane waves, with different timing characteristics. Simulation studies revealed potentially severe degradations in the retrospective focusing process, where both radial and lateral resolution was reduced, lateral shifts of the imaged medium were introduced, and losses in signal-to-noise ratio (SNR) were inferred. For myocardial imaging, physiological tissue displacements were on the order of half a wavelength, leading to SNR losses up to 35 dB, and reductions of contrast by 40 dB. No significant difference was observed between the different tilt sequences. A motion compensation technique based on cross-correlation was introduced, which significantly recovered the losses in SNR and contrast for physiological tissue velocities. Worst case losses in SNR and contrast were recovered by 35 dB and 27-35 dB, respectively. The effects of motion were demonstrated in vivo when imaging a rat heart. Using PWI, very high frame rates up to 463 fps were achieved at high image quality, but a motion correction scheme was then required.


Assuntos
Ecocardiografia/métodos , Processamento de Imagem Assistida por Computador/métodos , Algoritmos , Animais , Simulação por Computador , Movimento/fisiologia , Imagens de Fantasmas , Ratos , Razão Sinal-Ruído
16.
J Magn Reson Imaging ; 38(6): 1388-94, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23559475

RESUMO

PURPOSE: To evaluate late gadolinium-enhanced (LGE) assessment of infarct size, a comparison with manganese-enhanced magnetic resonance imaging (MEMRI), and histology was performed in a permanent infarction model in the mouse at the acute and chronic stage. MATERIALS AND METHODS: In a paired fashion at the acute and chronic stage after infarction (3-4 days and 21 days, respectively), LGE and MEMRI was performed using a self-gated fast low flip angle shot (FLASH). Infarct size was evaluated as the enhanced area relative to the complete myocardial wall area in a mid-ventricular slice. Paired comparisons were made between contrast agents and between timepoints, as well as to histology. RESULTS: At the acute stage, LGE delineated a larger infarct size as compared to both MEMRI and histology. Infarct size from LGE decreased from the acute to chronic stage, a temporal development not seen with MEMRI. At the chronic stage, no significant differences in infarct size were found between the methods. CONCLUSION: This study indicates an overenhancement of infarct size when using LGE, supported by an initial overestimation at the acute stage and a temporal decrease in infarct size from the acute to chronic stage, as compared to infarct size from MEMRI.


Assuntos
Técnicas de Imagem de Sincronização Cardíaca/métodos , Gadolínio DTPA/administração & dosagem , Aumento da Imagem/métodos , Cloreto de Magnésio/administração & dosagem , Infarto do Miocárdio/patologia , Algoritmos , Animais , Meios de Contraste/administração & dosagem , Feminino , Interpretação de Imagem Assistida por Computador/métodos , Estudos Longitudinais , Camundongos , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
Circ Res ; 110(11): 1474-83, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22511749

RESUMO

RATIONALE: Increased activity of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is thought to promote heart failure (HF) progression. However, the importance of CaMKII phosphorylation of ryanodine receptors (RyR2) in HF development and associated diastolic sarcoplasmic reticulum Ca(2+) leak is unclear. OBJECTIVE: Determine the role of CaMKII phosphorylation of RyR2 in patients and mice with nonischemic and ischemic forms of HF. METHODS AND RESULTS: Phosphorylation of the primary CaMKII site S2814 on RyR2 was increased in patients with nonischemic, but not with ischemic, HF. Knock-in mice with an inactivated S2814 phosphorylation site were relatively protected from HF development after transverse aortic constriction compared with wild-type littermates. After transverse aortic constriction, S2814A mice did not exhibit pulmonary congestion and had reduced levels of atrial natriuretic factor. Cardiomyocytes from S2814A mice exhibited significantly lower sarcoplasmic reticulum Ca(2+) leak and improved sarcoplasmic reticulum Ca(2+) loading compared with wild-type mice after transverse aortic constriction. Interestingly, these protective effects on cardiac contractility were not observed in S2814A mice after experimental myocardial infarction. CONCLUSIONS: Our results suggest that increased CaMKII phosphorylation of RyR2 plays a role in the development of pathological sarcoplasmic reticulum Ca(2+) leak and HF development in nonischemic forms of HF such as transverse aortic constriction in mice.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Adulto , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Técnicas de Introdução de Genes , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Mutação , Contração Miocárdica , Isquemia Miocárdica/complicações , Isquemia Miocárdica/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Retículo Sarcoplasmático/metabolismo , Serina , Fatores de Tempo , Regulação para Cima , Função Ventricular Esquerda , Pressão Ventricular , Remodelação Ventricular
18.
Eur J Appl Physiol ; 112(2): 579-88, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21614506

RESUMO

Activation of the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a critical role modulating cardiac function in both health and disease. Here, we determined the effect of chronic CaMKII inhibition during an exercise training program in healthy mice. CaMKII was inhibited by KN-93 injections. Mice were randomized to the following groups: sham sedentary, sham exercise, KN-93 sedentary, and KN-93 exercise. Cardiorespiratory function was evaluated by ergospirometry during treadmill running, echocardiography, and cardiomyocyte fractional shortening and calcium handling. The results revealed that KN-93 alone had no effect on exercise capacity or fractional shortening. In sham animals, exercise training increased maximal oxygen uptake by 8% (p < 0.05) compared to a 22% (p < 0.05) increase after exercise in KN-93 treated mice (group difference p < 0.01). In contrast, in vivo fractional shortening evaluated by echocardiography improved after exercise in sham animals only: from 25 to 32% (p < 0.02). In inactive mice, KN-93 reduced rates of diastolic cardiomyocyte re-lengthening (by 25%, p < 0.05) as well as Ca(2+) transient decay (by 16%, p < 0.05), whereas no such effect was observed after exercise training. KN-93 blunted exercise training response on cardiomyocyte fractional shortening (63% sham vs. 18% KN-93; p < 0.01 and p < 0.05, respectively). These effects could not be solely explained by the Ca(2+) transient amplitude, as KN-93 reduced it by 20% (p < 0.05) and response to exercise training was equal (64% sham and 47% KN-93; both p < 0.01). We concluded that chronic CaMKII inhibition increased time to 50% re-lengthening which were recovered by exercise training, but paradoxically led to a greater increase in maximal oxygen uptake compared to sham mice. Thus, the effect of chronic CaMKII inhibition is multifaceted and of a complex nature.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Contração Miocárdica/fisiologia , Condicionamento Físico Animal/métodos , Esforço Físico/fisiologia , Animais , Benzilaminas/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Esforço Físico/efeitos dos fármacos , Sulfonamidas/farmacologia
19.
Circ Res ; 109(10): 1162-72, 2011 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-21921265

RESUMO

RATIONALE: Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity. OBJECTIVES: Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis). METHODS AND RESULTS: Laboratory rats of widely diverse genetic backgrounds (N:NIH stock) were selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO(2max)), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats (hazard ratio, 0.06; P<0.001). VO(2max), measured across adulthood was a reliable predictor of lifespan (P<0.001). During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca(2+) handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (Vo(2)), and lean body mass were all better sustained with age in rats bred for high aerobic capacity. CONCLUSIONS: These data obtained from a contrasting heterogeneous model system provide strong evidence that genetic segregation for aerobic exercise capacity can be linked with longevity and are useful for deeper mechanistic exploration of aging.


Assuntos
Envelhecimento/fisiologia , Longevidade , Resistência Física , Envelhecimento/genética , Animais , Pressão Sanguínea , Composição Corporal , Peso Corporal , Sinalização do Cálcio , Metabolismo Energético , Feminino , Genótipo , Ventrículos do Coração/anatomia & histologia , Ventrículos do Coração/metabolismo , Longevidade/genética , Masculino , Contração Miocárdica , Consumo de Oxigênio , Fenótipo , Resistência Física/genética , Ratos , Corrida , Função Ventricular Esquerda
20.
World J Urol ; 28(4): 479-85, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20376453

RESUMO

PURPOSE: siRNA has been used successfully in loss-of-function studies in vitro, but neither in vivo nor in clinical applications. The aims of the present study were (1) to establish rat models for in vivo delivery of siRNA to bladder cancer, and (2) to identify potential targets for siRNA. METHODS: The rat models of human urinary carcinoma and rat urinary carcinoma cell line (AY-27) were induced by tobacco-related chemical carcinogens, either N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). A syngeneic orthotopic bladder cancer model was established by inoculation of AY-27 cells. A fluorescence-labelled negative control siRNA with cationic and neutral liposomes was tested both in vitro (AY-27 cells) and in vivo. RESULTS: siRNA was highly accumulated in the cancer cells as early as 12 h and remained at least for 24 h after a single dose in vivo. Numerous CD3+ T cells appeared mainly in the periphery area of the tumour. Bioinformatics analysis revealed a list of concordantly highly expressed genes, possible siRNA targets, in the animal models as well as human urinary carcinoma. Literature search on siRNA and bladder cancer provided a list of genes used as siRNA targets. CONCLUSION: The methodology and data presented in the present study provide a number of opportunities for basic research on urinary carcinogenesis and for translational research on evaluation of siRNA therapeutic strategies for urinary carcinoma in the native organ, where hormonal, neural and immunological processes more closely resemble the clinical situation.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética/métodos , RNA Interferente Pequeno/farmacologia , Neoplasias da Bexiga Urinária , Administração Intravesical , Animais , Biópsia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Corantes Fluorescentes , Ratos , Ratos Endogâmicos F344 , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia
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