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1.
Sci Rep ; 10(1): 15284, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943714

RESUMO

Acute myocardial ischaemia and reperfusion (I-R) are major causes of ventricular arrhythmias in patients with a history of coronary artery disease. Ursodeoxycholic acid (UDCA) has previously been shown to be antiarrhythmic in fetal hearts. This study was performed to investigate if UDCA protects against ischaemia-induced and reperfusion-induced arrhythmias in the adult myocardium, and compares the effect of acute (perfusion only) versus prolonged (2 weeks pre-treatment plus perfusion) UDCA administration. Langendorff-perfused adult Sprague-Dawley rat hearts were subjected to acute regional ischaemia by ligation of the left anterior descending artery (10 min), followed by reperfusion (2 min), and arrhythmia incidence quantified. Prolonged UDCA administration reduced the incidence of acute ischaemia-induced arrhythmias (p = 0.028), with a reduction in number of ventricular ectopic beats during the ischaemic phase compared with acute treatment (10 ± 3 vs 58 ± 15, p = 0.036). No antiarrhythmic effect was observed in the acute UDCA administration group. Neither acute nor prolonged UDCA treatment altered the incidence of reperfusion arrhythmias. The antiarrhythmic effect of UDCA may be partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity slowing (p = 0.03), and the preservation of Connexin43 phosphorylation during acute ischaemia (p = 0.0027). The potential antiarrhythmic effects of prolonged UDCA administration merit further investigation.

2.
Front Cell Dev Biol ; 8: 695, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850816

RESUMO

Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemic heart failure pointing to an autoimmune response against the heart. T and B cells have been convincingly demonstrated to be activated after myocardial infarction, a prerequisite for the generation of mature auto-antibodies. Yet, little is known about the immunoglobulin isotype repertoire thus pathological potential of anti-heart auto-antibodies during heart failure. We obtained human myocardial tissue from ischemic heart failure patients and induced experimental MI in rats. We found that anti-heart autoimmunity persists during heart failure. Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with mature isotype-switched IgG2a B cells. Mature IgG2a auto-antibodies specific for cardiac antigens are present in rat heart failure serum, and IgG and complement C3 deposits are evident in heart failure tissue of both rats and human patients. Previously established myocardial inflammation, and the herein provided proof of B cell maturation in lymph nodes and myocardial deposition of mature auto-antibodies, provide all the hallmark signs of an established autoimmune response in chronic heart failure.

3.
Cells ; 9(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31935926

RESUMO

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the blood vessel wall. Changes in VSMC actomyosin activity and morphology are prevalent in cardiovascular disease. The actin cytoskeleton actively defines cellular shape and the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, comprised of nesprin and the Sad1p, UNC-84 (SUN)-domain family members SUN1/2, has emerged as a key regulator of actin cytoskeletal organisation. Although SUN1 and SUN2 function is partially redundant, they possess specific functions and LINC complex composition is tailored for cell-type-specific functions. We investigated the importance of SUN1 and SUN2 in regulating actomyosin activity and cell morphology in VSMCs. We demonstrate that siRNA-mediated depletion of either SUN1 or SUN2 altered VSMC spreading and impaired actomyosin activity and RhoA activity. Importantly, these findings were recapitulated using aortic VSMCs isolated from wild-type and SUN2 knockout (SUN2 KO) mice. Inhibition of actomyosin activity, using the rho-associated, coiled-coil-containing protein kinase1/2 (ROCK1/2) inhibitor Y27632 or blebbistatin, reduced SUN2 mobility in the nuclear envelope and decreased the association between SUN2 and lamin A, confirming that SUN2 dynamics and interactions are influenced by actomyosin activity. We propose that the LINC complex exists in a mechanical feedback circuit with RhoA to regulate VSMC actomyosin activity and morphology.

4.
Biochim Biophys Acta Mol Basis Dis ; 1864(4 Pt B): 1345-1355, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29317337

RESUMO

Cardiac dysfunction has an increased prevalence in diseases complicated by liver cirrhosis such as primary biliary cholangitis and primary sclerosing cholangitis. This observation has led to research into the association between abnormalities in bile acid metabolism and cardiac pathology. Approximately 50% of liver cirrhosis cases develop cirrhotic cardiomyopathy. Bile acids are directly implicated in this, causing QT interval prolongation, cardiac hypertrophy, cardiomyocyte apoptosis and abnormal haemodynamics of the heart. Elevated maternal serum bile acids in intrahepatic cholestasis of pregnancy, a disorder which causes an impaired feto-maternal bile acid gradient, have been associated with fatal fetal arrhythmias. The hydrophobicity of individual bile acids in the serum bile acid pool is of relevance, with relatively lipophilic bile acids having a more harmful effect on the heart. Ursodeoxycholic acid can reverse or protect against these detrimental cardiac effects of elevated bile acids.


Assuntos
Arritmias Cardíacas/etiologia , Ácidos e Sais Biliares/metabolismo , Cardiomiopatias/etiologia , Colangite/metabolismo , Colestase Intra-Hepática/complicações , Cirrose Hepática Biliar/metabolismo , Apoptose/efeitos dos fármacos , Arritmias Cardíacas/prevenção & controle , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/química , Cardiomiopatias/sangue , Cardiomiopatias/epidemiologia , Cardiomiopatias/prevenção & controle , Colagogos e Coleréticos/farmacologia , Colagogos e Coleréticos/uso terapêutico , Colangite/sangue , Colangite/complicações , Colangite/tratamento farmacológico , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/tratamento farmacológico , Colestase Intra-Hepática/metabolismo , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Troca Materno-Fetal , Miócitos Cardíacos/patologia , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/metabolismo , Prevalência , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico
5.
Exp Cell Res ; 345(2): 168-79, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27321956

RESUMO

The spatial compartmentalisation of biochemical signalling pathways is essential for cell function. Nesprins are a multi-isomeric family of proteins that have emerged as signalling scaffolds, herein, we investigate the localisation and function of novel nesprin-2 N-terminal variants. We show that these nesprin-2 variants display cell specific distribution and reside in both the cytoplasm and nucleus. Immunofluorescence microscopy revealed that nesprin-2 N-terminal variants colocalised with ß-catenin at cell-cell junctions in U2OS cells. Calcium switch assays demonstrated that nesprin-2 and ß-catenin are lost from cell-cell junctions in low calcium conditions whereas emerin localisation at the NE remained unaltered, furthermore, an N-terminal fragment of nesprin-2 was sufficient for cell-cell junction localisation and interacted with ß-catenin. Disruption of these N-terminal nesprin-2 variants, using siRNA depletion resulted in loss of ß-catenin from cell-cell junctions, nuclear accumulation of active ß-catenin and augmented ß-catenin transcriptional activity. Importantly, we show that U2OS cells lack nesprin-2 giant, suggesting that the N-terminal nesprin-2 variants regulate ß-catenin signalling independently of the NE. Together, these data identify N-terminal nesprin-2 variants as novel regulators of ß-catenin signalling that tether ß-catenin to cell-cell contacts to inhibit ß-catenin transcriptional activity.


Assuntos
Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Humanos , Junções Intercelulares/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Ligação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Transporte Proteico , Reprodutibilidade dos Testes , Transcrição Genética
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