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2.
Basic Res Cardiol ; 117(1): 45, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068416

RESUMO

Tachycardiomyopathy is characterised by reversible left ventricular dysfunction, provoked by rapid ventricular rate. While the knowledge of mitochondria advanced in most cardiomyopathies, mitochondrial functions await elucidation in tachycardiomyopathy. Pacemakers were implanted in 61 rabbits. Tachypacing was performed with 330 bpm for 10 days (n = 11, early left ventricular dysfunction) or with up to 380 bpm over 30 days (n = 24, tachycardiomyopathy, TCM). In n = 26, pacemakers remained inactive (SHAM). Left ventricular tissue was subjected to respirometry, metabolomics and acetylomics. Results were assessed for translational relevance using a human-based model: induced pluripotent stem cell derived cardiomyocytes underwent field stimulation for 7 days (TACH-iPSC-CM). TCM animals showed systolic dysfunction compared to SHAM (fractional shortening 37.8 ± 1.0% vs. 21.9 ± 1.2%, SHAM vs. TCM, p < 0.0001). Histology revealed cardiomyocyte hypertrophy (cross-sectional area 393.2 ± 14.5 µm2 vs. 538.9 ± 23.8 µm2, p < 0.001) without fibrosis. Mitochondria were shifted to the intercalated discs and enlarged. Mitochondrial membrane potential remained stable in TCM. The metabolite profiles of ELVD and TCM were characterised by profound depletion of tricarboxylic acid cycle intermediates. Redox balance was shifted towards a more oxidised state (ratio of reduced to oxidised nicotinamide adenine dinucleotide 10.5 ± 2.1 vs. 4.0 ± 0.8, p < 0.01). The mitochondrial acetylome remained largely unchanged. Neither TCM nor TACH-iPSC-CM showed relevantly increased levels of reactive oxygen species. Oxidative phosphorylation capacity of TCM decreased modestly in skinned fibres (168.9 ± 11.2 vs. 124.6 ± 11.45 pmol·O2·s-1·mg-1 tissue, p < 0.05), but it did not in isolated mitochondria. The pattern of mitochondrial dysfunctions detected in two models of tachycardiomyopathy diverges from previously published characteristic signs of other heart failure aetiologies.


Assuntos
Cardiomiopatias , Insuficiência Cardíaca , Disfunção Ventricular Esquerda , Animais , Cardiomiopatias/etiologia , Humanos , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Coelhos
3.
J Mol Cell Cardiol ; 138: 212-221, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31836540

RESUMO

BACKGROUND: Activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) is established as a central intracellular trigger for various cardiac pathologies such as hypertrophy, heart failure or arrhythmias in animals and humans suggesting CaMKII as a promising target protein for future medical treatments. However, the physiological role of CaMKII is scarcely well defined. AIM & METHODS: To investigate the role of CaMKII in hyperacute pressure overload, we evaluated the effects of pressure overload induced by transverse aortic constriction (TAC) on survival, cardiac function, protein expression and excitation-contraction coupling (ECC) in female WT littermate vs. AC3-I mice 2 days after TAC (2d post TAC). AC3-I mice express the CaMKII inhibitor autocamtide-3 related inhibitory peptide (AiP) under the control of the α-myosin heavy chain promotor in the heart. RESULTS: CaMKII activation is significantly increased in WT TAC vs. sham mice 2d post TAC. Interestingly, survival is significantly reduced in AC3-I animals within the first five days after TAC compared to WT TAC littermates, while systolic cardiac function is markedly reduced in AC3-I TAC vs. AC3-I sham mice, but preserved in WT TAC vs. WT sham mice. Proteins regulating ECC such as ryanodine receptors (RyR2) and phospholamban (PLB) are hypophosphorylated at their CaMKII phosphorylation site in AC3-I TAC mice, but hyperphosphorylated in WT TAC mice compared to controls. In isolated cardiomyocytes fractional shortening is significantly impaired in AC3-I compared to WT mice 2d post TAC, and CaMKII incubation with AiP mimics the AC3-I phenotype in cardiomyocytes from WT TAC mice in vitro. In summary, this suggests cardiac dysfunction due to CaMKII inhibition as a potential cause of increased mortality in AC3-I TAC mice. However, proarrhythmic spontaneous Ca2+ release events (SCR) appear less frequent in cardiomyocytes from AC3-I TAC mice than in WT TAC mice. CONCLUSIONS: Our data indicate that excessive CaMKII inhibition as present in AC3-I transgenic mice leads to an impaired adaptation of ECC to hyperacute pressure overload resulting in diminished cardiac contractility and increased death. Thus, our data suggest that in pressure overload the activation of CaMKII is a pivotal, but previously unknown part of hyperacute stress physiology in the heart, while CaMKII inhibition, albeit potentially antiarrhythmic, can be detrimental. This should be taken into account for future studies with CaMKII inhibitors as therapeutic agents.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Pressão , Animais , Aorta/patologia , Arritmias Cardíacas/complicações , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Cardiomegalia/complicações , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Constrição Patológica , Diástole , Ativação Enzimática , Camundongos , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Peptídeos/metabolismo , Fosforilação , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Análise de Sobrevida
7.
FEBS Open Bio ; 11(10): 2756-2762, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34403217

RESUMO

Adrenergic stimulation, while being the central mechanism of cardiac positive inotropy, is a universally acknowledged inductor of undesirable sarcoplasmic reticulum (SR) Ca2+ leak. However, the exact mechanisms for this remained unspecified so far. This study shows that Ca2+ /calmodulin-dependent protein kinase II (CaMKII)-specific phosphorylation of ryanodine receptor type 2 at Ser-2814 is the pivotal mechanism by which SR Ca2+ leak develops downstream of ß1-adrenergic stress by increase of the leak/load relationship. Cardiomyocytes with a Ser-2814 phosphoresistant mutation (S2814A) were protected from isoproterenol-induced SR Ca2+ leak and consequently displayed improved postrest potentiation of systolic Ca2+ release under adrenergic stress compared to littermate wild-type cells.


Assuntos
Canal de Liberação de Cálcio do Receptor de Rianodina , Retículo Sarcoplasmático , Adrenérgicos/metabolismo , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Fosforilação , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo
8.
Front Immunol ; 12: 740260, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745111

RESUMO

Increased left ventricular fibrosis has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). It is unclear whether this fibrosis is a consequence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection or a risk factor for severe disease progression. We observed increased fibrosis in the left ventricular myocardium of deceased COVID-19 patients, compared with matched controls. We also detected increased mRNA levels of soluble interleukin-1 receptor-like 1 (sIL1-RL1) and transforming growth factor ß1 (TGF-ß1) in the left ventricular myocardium of deceased COVID-19 patients. Biochemical analysis of blood sampled from patients admitted to the emergency department (ED) with COVID-19 revealed highly elevated levels of TGF-ß1 mRNA in these patients compared to controls. Left ventricular strain measured by echocardiography as a marker of pre-existing cardiac fibrosis correlated strongly with blood TGF-ß1 mRNA levels and predicted disease severity in COVID-19 patients. In the left ventricular myocardium and lungs of COVID-19 patients, we found increased neuropilin-1 (NRP-1) RNA levels, which correlated strongly with the prevalence of pulmonary SARS-CoV-2 nucleocapsid. Cardiac and pulmonary fibrosis may therefore predispose these patients to increased cellular viral entry in the lung, which may explain the worse clinical outcome observed in our cohort. Our study demonstrates that patients at risk of clinical deterioration can be identified early by echocardiographic strain analysis and quantification of blood TGF-ß1 mRNA performed at the time of first medical contact.


Assuntos
COVID-19/fisiopatologia , Ventrículos do Coração/patologia , Miocárdio/patologia , Fibrose Pulmonar/fisiopatologia , SARS-CoV-2/fisiologia , Adulto , Idoso , COVID-19/imunologia , Feminino , Fibrose , Ventrículos do Coração/metabolismo , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Neuropilina-1/genética , Neuropilina-1/metabolismo , Fibrose Pulmonar/imunologia , Risco , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Carga Viral
9.
ESC Heart Fail ; 8(1): 309-316, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33215884

RESUMO

AIMS: We aimed to assess whether expression of whole-blood RNA of sodium proton exchanger 1 (NHE1) and glucose transporter 1 (GLUT1) is associated with COVID-19 infection and outcome in patients presenting to the emergency department with respiratory infections. Furthermore, we investigated NHE1 and GLUT1 expression in the myocardium of deceased COVID-19 patients. METHODS AND RESULTS: Whole-blood quantitative assessment of NHE1 and GLUT1 RNA was performed using quantitative PCR in patients with respiratory infection upon first contact in the emergency department and subsequently stratified by SARS-CoV-2 infection status. Assessment of NHE1 and GLUT1 RNA using PCR was also performed in left ventricular myocardium of deceased COVID-19 patients. NHE1 expression is up-regulated in whole blood of patients with COVID-19 compared with other respiratory infections at first medical contact in the emergency department (control: 0.0021 ± 0.0002, COVID-19: 0.0031 ± 0.0003, P = 0.01). The ratio of GLUT1 to NHE1 is significantly decreased in the blood of COVID-19 patients who are subsequently intubated and/or die (severe disease) compared with patients with moderate disease (moderate disease: 0.497 ± 0.083 vs. severe disease: 0.294 ± 0.0336, P = 0.036). This ratio is even further decreased in the myocardium of patients who deceased from COVID-19 in comparison with the myocardium of non-infected donors. CONCLUSIONS: NHE1 and GLUT1 may be critically involved in the disease progression of SARS-CoV-2 infection. We show here that SARS-CoV-2 infection critically disturbs ion channel expression in the heart. A decreased ratio of GLUT1/NHE1 could potentially serve as a biomarker for disease severity in patients with COVID-19.


Assuntos
COVID-19/metabolismo , Transportador de Glucose Tipo 1/sangue , Trocador 1 de Sódio-Hidrogênio/sangue , COVID-19/sangue , COVID-19/diagnóstico , Estudos de Casos e Controles , Serviço Hospitalar de Emergência , Feminino , Transportador de Glucose Tipo 1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Estudos Prospectivos , RNA Mensageiro/sangue , Índice de Gravidade de Doença , Trocador 1 de Sódio-Hidrogênio/metabolismo
10.
Invest Ophthalmol Vis Sci ; 58(1): 394-403, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28118664

RESUMO

Purpose: Stargardt disease (STGD1) is an autosomal recessive retinopathy, caused by mutations in the retina-specific ATP-binding cassette transporter (ABCA4) gene. To establish the mutational spectrum and to assess effects of selected deep intronic and common genetic variants on disease, we performed a comprehensive sequence analysis in a large cohort of German STGD1 patients. Methods: DNA samples of 335 STGD1 patients were analyzed for ABCA4 mutations in its 50 coding exons and adjacent intronic sequences by resequencing array technology or next generation sequencing (NGS). Parts of intron 30 and 36 were screened by Sanger chain-terminating dideoxynucleotide sequencing. An in vitro splicing assay was used to test selected variants for their splicing behavior. By logistic regression analysis we assessed the association of common ABCA4 alleles while a multivariate logistic regression model calculated a genetic risk score (GRS). Results: Our analysis identified 148 pathogenic or likely pathogenic mutations, of which 48 constitute so far unpublished ABCA4-associated disease alleles. Four rare deep intronic variants were found once in 472 alleles analyzed. In addition, we identified six risk-modulating common variants. Genetic risk score estimates suggest that defined common ABCA4 variants influence disease risk in carriers of a single pathogenic ABCA4 allele. Conclusions: Our study adds to the mutational spectrum of the ABCA4 gene. Moreover, in our cohort, deep intronic variants in intron 30 and 36 likely play no or only a minor role in disease pathology. Of note, our findings demonstrate a possible modifying effect of common sequence variants on ABCA4-associated disease.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , DNA/genética , Degeneração Macular/congênito , Mutação , Transportadores de Cassetes de Ligação de ATP/metabolismo , Alelos , Análise Mutacional de DNA , Éxons , Feminino , Seguimentos , Humanos , Íntrons , Degeneração Macular/genética , Degeneração Macular/metabolismo , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Doença de Stargardt
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