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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.
J Am Heart Assoc ; 7(20): e010025, 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30371289

RESUMO

Background Mechanical stimulation of acute ischemic myocardium by shock wave therapy ( SWT ) is known to improve cardiac function by induction of angiogenesis. However, SWT in chronic heart failure is poorly understood. We aimed to study whether mechanical stimulation upon SWT improves heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis and to dissect underlying mechanisms. Methods and Results SWT was applied in a mouse model of chronic myocardial ischemia. To study effects of SWT on postnatal vasculogenesis, wild-type mice received bone marrow transplantation from green fluorescence protein donor mice. Underlying mechanisms were elucidated in vitro in endothelial cells and murine aortic rings. Echocardiography and pressure/volume measurements revealed improved left ventricular ejection fraction, myocardial contractility, and diastolic function and decreased myocardial fibrosis after treatment. Concomitantly, numbers of capillaries and arterioles were increased. SWT resulted in enhanced expression of the chemoattractant stromal cell-derived factor 1 in ischemic myocardium and serum. Treatment induced recruitment of bone marrow-derived endothelial cells to the site of injury. In vitro, SWT resulted in endothelial cell proliferation, enhanced survival, and capillary sprouting. The effects were vascular endothelial growth factor receptor 2 and heparan sulfate proteoglycan dependent. Conclusions SWT positively affects heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis. SWT upregulated pivotal angiogenic and vasculogenic factors in the myocardium in vivo and induced proliferative and anti-apoptotic effects on endothelial cells in vitro. Mechanistically, these effects depend on vascular endothelial growth factor signaling and heparan sulfate proteoglycans. SWT is a promising treatment option for regeneration of ischemic myocardium.

3.
J Mol Cell Cardiol ; 115: 10-19, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29289652

RESUMO

Heart failure (HF) with preserved ejection fraction (HFpEF) is present in about 50% of HF patients. Atrial remodeling is common in HFpEF and associated with increased mortality. We postulate that atrial remodeling is associated with atrial dysfunction in vivo related to alterations in cardiomyocyte Calcium (Ca) signaling and remodeling. We examined atrial function in vivo and Ca transients (CaT) (Fluo4-AM, field stim) in atrial cardiomyocytes of ZSF-1 rats without (Ln; lean hypertensive) and with metabolic syndrome (Ob; obese, hypertensive, diabetic) and HFpEF. RESULTS: At 21weeks Ln showed an increased left ventricular (LV) mass and left ventricular end-diastolic pressure (LVEDP), but unchanged left atrial (LA) size and preserved atrial ejection fraction vs. wild-type (WT). CaT amplitude in atrial cardiomyocytes was increased in Ln (2.9±0.2 vs. 2.3±0.2F/F0 in WT; n=22 cells/group; p<0.05). Studying subcellular Ca release in more detail, we found that local central cytosolic CaT amplitude was increased, while subsarcolemmal CaT amplitudes remained unchanged. Moreover, Sarcoplasmic reticulum (SR) Ca content (caffeine) was preserved while Ca spark frequency and tetracaine-dependent SR Ca leak were significantly increased in Ln. Ob mice developed a HFpEF phenotype in vivo, LA area was significantly increased and atrial in vivo function was impaired, despite increased atrial CaT amplitudes in vitro (2.8±0.2; p<0.05 vs. WT). Ob cells showed alterations of the tubular network possibly contributing to the observed phenotype. CaT kinetics as well as SR Ca in Ob were not significantly different from WT, but SR Ca leak remained increased. Angiotensin II (Ang II) reduced in vitro cytosolic CaT amplitudes and let to active nuclear Ca release in Ob but not in Ln or WT. SUMMARY: In hypertensive ZSF-1 rats, a possibly compensatory increase of cytosolic CaT amplitude and increased SR Ca leak precede atrial remodeling and HFpEF. Atrial remodeling in ZSF-1 HFpEF is associated with an altered tubular network in-vitro and atrial contractile dysfunction in vivo, indicating insufficient compensation. Atrial cardiomyocyte dysfunction in vitro is induced by the addition of angiotensin II.

4.
J Cell Mol Med ; 21(4): 791-801, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27995765

RESUMO

Shock wave treatment (SWT) was shown to induce regeneration of ischaemic myocardium via Toll-like receptor 3 (TLR3). The antimicrobial peptide LL37 gets released by mechanical stress and is known to form complexes with nucleic acids thus activating Toll-like receptors. We suggested that SWT in the acute setting prevents from the development of heart failure via RNA/protein release. Myocardial infarction in mice was induced followed by subsequent SWT. Heart function was assessed 4 weeks later via transthoracic echocardiography and pressure-volume measurements. Human umbilical vein endothelial cells (HUVECs) were treated with SWT in the presence of RNase and proteinase and analysed for proliferation, tube formation and LL37 expression. RNA release and uptake after SWT was evaluated. We found significantly improved cardiac function after SWT. SWT resulted in significantly higher numbers of capillaries and arterioles and less left ventricular fibrosis. Supernatants of treated cells activated TLR3 reporter cells. Analysis of the supernatant revealed increased RNA levels. The effect could not be abolished by pre-treatment of the supernatant with RNase, but only by a sequential digestion with proteinase and RNase hinting strongly towards the involvement of RNA/protein complexes. Indeed, LL37 expression as well as cellular RNA uptake were significantly increased after SWT. We show for the first time that SWT prevents from left ventricular remodelling and cardiac dysfunction via RNA/protein complex release and subsequent induction of angiogenesis. It might therefore develop a potent regenerative treatment alternative for ischaemic heart disease.


Assuntos
Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/terapia , Ondas de Choque de Alta Energia , Isquemia Miocárdica/complicações , Isquemia Miocárdica/terapia , Proteínas/metabolismo , RNA/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos , Catelicidinas/metabolismo , Cicatriz/patologia , Endocitose , Insuficiência Cardíaca/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/metabolismo , Neovascularização Fisiológica
5.
Nat Med ; 22(12): 1428-1438, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27841876

RESUMO

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.


Assuntos
Envelhecimento/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Coração/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Degradação Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Espermidina/farmacologia , Adulto , Idoso , Envelhecimento/imunologia , Envelhecimento/metabolismo , Animais , Proteína 5 Relacionada à Autofagia/genética , Cardiomegalia/diagnóstico por imagem , Cardiotônicos/farmacologia , Doenças Cardiovasculares/epidemiologia , Cromatografia Líquida de Alta Pressão , Conectina/efeitos dos fármacos , Conectina/metabolismo , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Diástole , Dieta/estatística & dados numéricos , Ecocardiografia , Feminino , Expressão Gênica/efeitos dos fármacos , Teste de Tolerância a Glucose , Coração/diagnóstico por imagem , Insuficiência Cardíaca , Humanos , Immunoblotting , Inflamação , Masculino , Espectrometria de Massas , Camundongos , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/metabolismo , Fosforilação/efeitos dos fármacos , Estudos Prospectivos , Ratos , Ratos Endogâmicos Dahl , Inquéritos e Questionários
6.
Eur J Heart Fail ; 18(8): 987-97, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27135883

RESUMO

AIMS: Heart failure with preserved ejection fraction (HFpEF) is increasingly common, but the underlying cellular mechanisms are not well understood. We investigated cardiomyocyte function and the role of SEA0400, an Na(+) /Ca(2+) exchanger (NCX) inhibitor in a rat model of chronic kidney disease (CKD) with HFpEF. METHODS AND RESULTS: Male Wistar rats were subjected to subtotal nephrectomy (NXT) or sham operation (Sham). After 8 and 24 weeks, in vivo (haemodynamics, echocardiography) and in vitro function (LV cardiomyocyte cell shortening (CS), and Ca(2+) transients (CaT)) were determined without and with SEA0400. In a subgroup of rats, SEA0400 or vehicle was given p.o. (1 mg/kg b.w.) between week 8 and 24. NXT resulted in stable compensated CKD and HFpEF [hypertrophied left ventricle, prolonged LV isovolumetric relaxation constant TAU (IVRc TAU), elevated end diastolic pressure (EDP), increased lung weight (pulmonary congestion), and preserved LV systolic function (EF, dP/dt)]. In NXT cardiomyocytes, the amplitude of CS and CaT were unchanged but relaxation and CaT decay were progressively prolonged at 8 and 24 weeks vs. Sham, individually correlating with diastolic dysfunction in vivo. NCX forward mode activity (caffeine response) was progressively reduced, while NCX protein expression was up-regulated, suggesting increased NCX reverse mode activity in NXT. SEA0400 acutely improved relaxation in NXT in vivo and in cardiomyocytes and improved cardiac remodelling and diastolic function when given chronically. CONCLUSIONS: This model of renal HFpEF is associated with slowed relaxation of LV cardiomyocytes. Treatment with SEA0400 improved cardiomyocyte function, remodelling, and HFpEF.


Assuntos
Compostos de Anilina/farmacologia , Insuficiência Cardíaca/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Éteres Fenílicos/farmacologia , Insuficiência Renal Crônica/fisiopatologia , Trocador de Sódio e Cálcio/antagonistas & inibidores , Volume Sistólico , Animais , Cafeína/farmacologia , Cálcio/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Ecocardiografia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/complicações
7.
J Mol Cell Cardiol ; 97: 36-43, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27106803

RESUMO

AMP-activated protein kinase (Ampk) regulates myocardial energy metabolism and plays a crucial role in the response to cell stress. In the failing heart, an isoform shift of the predominant Ampkα2 to the Ampkα1 was observed. The present study explored possible isoform specific effects of Ampkα1 in cardiomyocytes. To this end, experiments were performed in HL-1 cardiomyocytes, as well as in Ampkα1-deficient and corresponding wild-type mice and mice following AAV9-mediated cardiac overexpression of constitutively active Ampkα1. As a result, in HL-1 cardiomyocytes, overexpression of constitutively active Ampkα1 increased the phosphorylation of Pkcζ. Constitutively active Ampkα1 further increased AP-1-dependent transcriptional activity and mRNA expression of the AP-1 target genes c-Fos, Il6 and Ncx1, effects blunted by Pkcζ silencing. In HL-1 cardiomyocytes, angiotensin-II activated AP-1, an effect blunted by silencing of Ampkα1 and Pkcζ, but not of Ampkα2. In wild-type mice, angiotensin-II infusion increased cardiac Ampkα1 and cardiac Pkcζ protein levels, as well as c-Fos, Il6 and Ncx1 mRNA expression, effects blunted in Ampkα1-deficient mice. Pressure overload by transverse aortic constriction (TAC) similarly increased cardiac Ampkα1 and Pkcζ abundance as well as c-Fos, Il6 and Ncx1 mRNA expression, effects again blunted in Ampkα1-deficient mice. AAV9-mediated cardiac overexpression of constitutively active Ampkα1 increased Pkcζ protein abundance and the mRNA expression of c-Fos, Il6 and Ncx1 in cardiac tissue. In conclusion, Ampkα1 promotes myocardial AP-1 activation in a Pkcζ-dependent manner and thus contributes to cardiac stress signaling.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Miócitos Cardíacos/metabolismo , Fator de Transcrição AP-1/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Dependovirus/genética , Expressão Gênica , Vetores Genéticos/genética , Camundongos , Camundongos Knockout , Isoformas de Proteínas , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Transdução de Sinais , Transdução Genética
8.
Cell Physiol Biochem ; 35(1): 406-18, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25591781

RESUMO

BACKGROUND/AIMS: Adenosine 5'-monophosphate (AMP)-activated protein kinase (Ampk) modulates a wide array of cellular functions and regulates various ion channels and transporters. In failing human hearts an increased Ampkα1 activity was observed. The present study aimed to uncover the impact of Ampkα1 on cardiac electrical remodeling. METHODS: Gene-targeted mice lacking functional Ampkα1 (Ampkα1-/-) and corresponding wild-type mice were exposed to pressure overload by "transverse aortic constriction" (TAC). In vivo electrophysiology was performed with a single catheter technique, myocardial conduction velocities and conduction characteristics investigated in isolated hearts, transcript levels quantified by RT-PCR and protein abundance determined by Western blotting. Moreover, connexin 43 (Cx43) was expressed in Xenopus oocytes with or without coexpression of wild-type or mutant AMPK and Cx43 protein abundance quantified utilizing confocal microscopy. RESULTS: TAC treatment increased Ampkα1 protein expression in cardiac tissue from wild-type mice. TAC further increased left ventricular conduction inhomogeneity and triggered conduction blocks, effects blunted in the Ampkα1(-/-) mice. TAC treatment decreased Cx43 protein abundance in cardiac tissue, an effect significantly blunted in the Ampkα1(-/-) mice. TAC treatment did not modify Cx43 mRNA levels but increased ubiquitination of Cx43 protein, an effect mitigated by Ampkα1 deficiency. As shown in Xenopus oocytes, Cx43 cell membrane protein abundance was significantly downregulated by wild-type AMPK(WT) and constitutively active AMPK(γR70Q), but not by catalytically inactive AMPK(αK45R). CONCLUSION: Ampkα1 stimulates ubiquitination of the gap junction protein Cx43, thereby contributing to gap junction remodeling following pressure overload.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Conexina 43/metabolismo , Proteínas Quinases Ativadas por AMP/deficiência , Proteínas Quinases Ativadas por AMP/genética , Substituição de Aminoácidos , Animais , Remodelamento Atrial , Conexina 43/genética , Regulação para Baixo , Fenômenos Eletrofisiológicos , Camundongos , Camundongos Knockout , Microscopia Confocal , Miocárdio/metabolismo , Oócitos/metabolismo , Pressão , RNA Mensageiro/metabolismo , Ubiquitinação , Xenopus/crescimento & desenvolvimento
9.
Cardiovasc Res ; 106(1): 163-73, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25631581

RESUMO

AIM: TRPC3 is a non-selective cation channel, which forms a Ca2+ entry pathway involved in cardiac remodelling. Our aim was to analyse acute electrophysiological and contractile consequences of TRPC3 activation in the heart. METHODS AND RESULTS: We used a murine model of cardiac TRPC3 overexpression and a novel TRPC3 agonist, GSK1702934A, to uncover (patho)physiological functions of TRPC3. GSK1702934A induced a transient, non-selective conductance and prolonged action potentials in TRPC3-overexpressing myocytes but lacked significant electrophysiological effects in wild-type myocytes. GSK1702934A transiently enhanced contractility and evoked arrhythmias in isolated Langendorff hearts from TRPC3-overexpressing but not wild-type mice. Interestingly, pro-arrhythmic effects outlasted TRPC3 current activation, were prevented by enhanced intracellular Ca2+ buffering, and suppressed by the NCX inhibitor 3',4'-dichlorobenzamil hydrochloride. GSK1702934A substantially promoted NCX currents in TRPC3-overexpressing myocytes. The TRPC3-dependent electrophysiologic, pro-arrhythmic, and inotropic actions of GSK1702934A were mimicked by angiotensin II (AngII). Immunocytochemistry demonstrated colocalization of TRPC3 with NCX1 and disruption of local interaction upon channel activation by either GSK1702934A or AngII. CONCLUSION: Cardiac TRPC3 mediates Ca2+ and Na+ entry in proximity of NCX1, thereby elevating cellular Ca2+ levels and contractility. Excessive activation of TRPC3 is associated with transient cellular Ca2+ overload, spatial uncoupling between TRPC3 and NCX1, and arrhythmogenesis. We propose TRPC3-NCX micro/nanodomain communication as determinant of cardiac contractility and susceptibility to arrhythmogenic stimuli.


Assuntos
Arritmias Cardíacas/fisiopatologia , Contração Miocárdica/fisiologia , Transdução de Sinais/fisiologia , Trocador de Sódio e Cálcio/fisiologia , Canais de Cátion TRPC/fisiologia , Potenciais de Ação/fisiologia , Animais , Arritmias Cardíacas/patologia , Cálcio/fisiologia , Modelos Animais de Doenças , Técnicas Eletrofisiológicas Cardíacas , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Técnicas de Patch-Clamp , Canais de Cátion TRPC/agonistas , Canais de Cátion TRPC/genética
10.
Heart ; 99(22): 1685-92, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23894089

RESUMO

OBJECTIVE: High bile acid serum concentrations have been implicated in cardiac disease, particularly in arrhythmias. Most data originate from in vitro studies and animal models. We tested the hypotheses that (1) high bile acid concentrations are arrhythmogenic in adult human myocardium, (2) serum bile acid concentrations and composition are altered in patients with atrial fibrillation (AF) and (3) the therapeutically used ursodeoxycholic acid has different effects than other potentially toxic bile acids. METHODS AND RESULTS: Multicellular human atrial preparations ('trabeculae') were exposed to primary bile acids and the incidence of arrhythmic events was assessed. Bile acid concentrations were measured in serum samples from 250 patients and their association with AF and ECG parameters analysed. Additionally, we conducted electrophysiological studies in murine myocytes. Taurocholic acid (TCA) concentration-dependently induced arrhythmias in atrial trabeculae (14/28 at 300 µM TCA, p<0.01) while ursodeoxycholic acid did not. Patients with AF had significantly decreased serum levels of ursodeoxycholic acid conjugates and increased levels of non-ursodeoxycholic bile acids. In isolated myocytes, TCA depolarised the resting membrane potential, enhanced Na(+)/Ca(2+) exchanger (NCX) tail current density and induced afterdepolarisations. Inhibition of NCX prevented arrhythmias in atrial trabeculae. CONCLUSIONS: High TCA concentrations induce arrhythmias in adult human atria while ursodeoxycholic acid does not. AF is associated with higher serum levels of non-ursodeoxycholic bile acid conjugates and low levels of ursodeoxycholic acid conjugates. These data suggest that higher levels of toxic (arrhythmogenic) and low levels of protective bile acids create a milieu with a decreased arrhythmic threshold and thus may facilitate arrhythmic events.


Assuntos
Fibrilação Atrial/sangue , Fibrilação Atrial/etiologia , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/farmacologia , Átrios do Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Idoso , Animais , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/fisiologia , Eletrofisiologia Cardíaca , Feminino , Humanos , Masculino , Camundongos , Ácido Taurocólico/farmacologia , Ácido Ursodesoxicólico/farmacologia
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