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1.
Circulation ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31315456

RESUMO

BACKGROUND: Plakophilin-2 (PKP2) is classically defined as a desmosomal protein. Mutations in PKP2 associate with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy (ARVC). A better understanding of PKP2 cardiac biology can help elucidate the mechanisms underlying arrhythmic and cardiomyopathic events consequent to PKP2 deficiency. Here, we sought to capture early molecular/cellular events that can act as nascent arrhythmic/cardiomyopathic substrates. METHODS: We used multiple imaging, biochemical and high-resolution mass spectrometry methods to study functional/structural properties of cells/tissues derived from cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mice ("PKP2cKO") 14 days post-tamoxifen (post-TAM) injection, a time point preceding overt electrical or structural phenotypes. Myocytes from right or left ventricular free wall were studied separately. RESULTS: Most properties of PKP2cKO left ventricular (PKP2cKO-LV) myocytes were not different from control; in contrast, PKP2cKO right ventricular (PKP2cKO-RV) myocytes showed increased amplitude and duration of Ca2+ transients, increased [Ca2+] in the cytoplasm and sarcoplasmic reticulum (SR), increased frequency of spontaneous Ca2+ release events (sparks) even at comparable SR load, and dynamic Ca2+ accumulation in mitochondria. We also observed early- and delayed-after transients in RV myocytes and heightened susceptibility to arrhythmias in Langendorff-perfused hearts. In addition, RyR2 in PKP2cKO-RV cells presented enhanced Ca2+ sensitivity and preferential phosphorylation in a domain known to modulate Ca2+ gating. RNAseq at 14 days post-TAM showed no relevant difference in transcript abundance between RV and LV, neither in control nor in PKP2cKO cells. Instead, we found an RV-predominant increase in membrane permeability that can permit Ca2+ entry into the cell. Cx43 ablation mitigated the membrane permeability increase, accumulation of cytoplasmic Ca2+, increased frequency of sparks and early stages of RV dysfunction. Cx43 hemichannel block with GAP19 normalized [Ca2+]i homeostasis. Similarly, PKC inhibition normalized spark frequency at comparable SR load levels. CONCLUSIONS: Loss of PKP2 creates an RV-predominant arrhythmogenic substrate (Ca2+ dysregulation) that precedes the cardiomyopathy; this is, at least in part, mediated by a Cx43-dependent membrane conduit and repressed by PKC inhibitors. Given that asymmetric Ca2+ dysregulation precedes the cardiomyopathic stage, we speculate that abnormal Ca2+ handling in RV myocytes can be a trigger for gross structural changes observed at a later stage.

2.
Am J Case Rep ; 20: 957-960, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31271565

RESUMO

BACKGROUND Gallstones are a common cause of acute pancreatitis. The proposed mechanism by which choledocholithiasis induces pancreatitis is mechanical obstruction of the ampulla leading to the reflux of bile into the pancreatic duct or edema resulting from a gallstone's passage. To our knowledge, there are no previously reported cases of gallbladder adenocarcinoma as a potential cause of acute pancreatitis. Herein, we describe a patient who presented with acute necrotizing pancreatitis, without other associated risk factors, who was found to have a fragmented friable polypoid gallbladder adenocarcinoma. CASE REPORT A 55-year old Hispanic female with prediabetes presented to the Emergency Department with severe epigastric abdominal pain radiating to her back. The patient's clinical presentation, laboratory tests and computed tomography imaging were suggestive of acute necrotizing pancreatitis and a gallbladder lesion concerning for neoplasm. After clinical resolution of her pancreatitis, the patient was brought to the operating room for a cholecystectomy. Final pathology revealed a stage T1aN0 gallbladder adenocarcinoma. CONCLUSIONS We have presented a patient with acute necrotizing pancreatitis in the absence of alcohol abuse, gallstones, biliary sludge, hypertriglyceridemia, hypercalcemia, or hereditary predisposition. Without evidence of other etiologies, we hypothesize that the friable tumor fragments of the gallbladder adenocarcinoma might be the underlying cause of pancreatitis in this patient.

3.
Elife ; 82019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30896405

RESUMO

Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adult-specific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca2+ homeostasis, providing a molecular mechanism underlying the genetic implication of TBX5 in AF. We show that cardiomyocyte action potential (AP) abnormalities in Tbx5-deficient atrial cardiomyocytes are caused by a decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2)-mediated SR calcium uptake which was balanced by enhanced trans-sarcolemmal calcium fluxes (calcium current and sodium/calcium exchanger), providing mechanisms for triggered activity. The AP defects, cardiomyocyte ectopy, and AF caused by TBX5 deficiency were rescued by phospholamban removal, which normalized SERCA function. These results directly link transcriptional control of SERCA2 activity, depressed SR Ca2+ sequestration, enhanced trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca2+-dependent pathway for AF risk.

4.
JCI Insight ; 52019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30835254

RESUMO

Hypertrophic cardiomyopathy (HCM) is triggered mainly by mutations in genes encoding sarcomeric proteins, but a significant proportion of patients lack a genetic diagnosis. We identified a novel mutation in the ryanodine receptor 2, RyR2-P1124L, in a patient from a genotype-negative HCM cohort. The aim of this study was to determine whether RyR2-P1124L triggers functional and structural alterations in isolated RyR2 channels and whole hearts. We found that P1124L induces significant conformational changes in the SPRY2 domain of RyR2. Recombinant RyR2-P1124L channels displayed a cytosolic loss-of-function phenotype, which contrasted with a higher sensitivity to luminal [Ca2+], indicating a luminal gain-of-function. Homozygous mice for RyR2-P1124L showed mild cardiac hypertrophy, similar to the human patient. This phenotype, evident at 1 yr of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 mo of age, before the onset of hypertrophy. RyR2-P1124L has a distinct cytosolic loss-of-function and a luminal gain-of-function phenotype. This bifunctionally-divergent behavior triggers arrhythmias and structural cardiac remodeling, and involves overexpression of calmodulin as a potential hypertrophic mediator. This study is relevant to continue elucidating the possible causes of genotype-negative HCM and the role of RyR2 in cardiac hypertrophy.

5.
6.
Circ Res ; 122(11): 1501-1516, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29514831

RESUMO

RATIONALE: In cardiomyocytes, NaV1.5 and Kir2.1 channels interact dynamically as part of membrane bound macromolecular complexes. OBJECTIVE: The objective of this study was to test whether NaV1.5 and Kir2.1 preassemble during early forward trafficking and travel together to common membrane microdomains. METHODS AND RESULTS: In patch-clamp experiments, coexpression of trafficking-deficient mutants Kir2.1Δ314-315 or Kir2.1R44A/R46A with wild-type (WT) NaV1.5WT in heterologous cells reduced inward sodium current compared with NaV1.5WT alone or coexpressed with Kir2.1WT. In cell surface biotinylation experiments, expression of Kir2.1Δ314-315 reduced NaV1.5 channel surface expression. Glycosylation analysis suggested that NaV1.5WT and Kir2.1WT channels associate early in their biosynthetic pathway, and fluorescence recovery after photobleaching experiments demonstrated that coexpression with Kir2.1 increased cytoplasmic mobility of NaV1.5WT, and vice versa, whereas coexpression with Kir2.1Δ314-315 reduced mobility of both channels. Viral gene transfer of Kir2.1Δ314-315 in adult rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes reduced inward rectifier potassium current and inward sodium current, maximum diastolic potential and action potential depolarization rate, and increased action potential duration. On immunostaining, the AP1 (adaptor protein complex 1) colocalized with NaV1.5WT and Kir2.1WT within areas corresponding to t-tubules and intercalated discs. Like Kir2.1WT, NaV1.5WT coimmunoprecipitated with AP1. Site-directed mutagenesis revealed that NaV1.5WT channels interact with AP1 through the NaV1.5Y1810 residue, suggesting that, like for Kir2.1WT, AP1 can mark NaV1.5 channels for incorporation into clathrin-coated vesicles at the trans-Golgi. Silencing the AP1 ϒ-adaptin subunit in human induced pluripotent stem cell-derived cardiomyocytes reduced inward rectifier potassium current, inward sodium current, and maximum diastolic potential and impaired rate-dependent action potential duration adaptation. CONCLUSIONS: The NaV1.5-Kir2.1 macromolecular complex pre-assembles early in the forward trafficking pathway. Therefore, disruption of Kir2.1 trafficking in cardiomyocytes affects trafficking of NaV1.5, which may have important implications in the mechanisms of arrhythmias in inheritable cardiac diseases.

7.
J Mol Cell Cardiol ; 114: 199-210, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29174767

RESUMO

Sorcin, a penta-EF hand Ca2+-binding protein expressed in cardiomyocytes, is known to interact with ryanodine receptors and other Ca2+ regulatory proteins. To investigate sorcin's influence on cardiac excitation-contraction coupling and its role in the development of cardiac malfunctions, we generated a sorcin knockout (KO) mouse model. Sorcin KO mice presented ventricular arrhythmia and sudden death when challenged by acute stress induced by isoproterenol plus caffeine. Chronic stress, which was induced by transverse aortic constriction, significantly decreased the survival rate of sorcin KO mice. Under isoproterenol stimulation, spontaneous Ca2+ release events were frequently observed in sorcin KO cardiomyocytes. Sorcin KO hearts of adult, but not young mice developed overexpression of L-type Ca2+ channel and Na+-Ca2+ exchanger, which enhanced ICa and INCX. Consequently, spontaneous Ca2+ release events in sorcin KO cardiomyocytes were more likely to induce arrhythmogenic delayed afterdepolarizations. Our study demonstrates sorcin deficiency may trigger cardiac ventricular arrhythmias due to Ca2+ disturbances, and evidences the critical role of sorcin in maintaining Ca2+ homeostasis, especially during the adrenergic response of the heart.

8.
Cardiovasc Res ; 113(13): 1688-1699, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29016724

RESUMO

Aims: Abnormal intracellular Ca2+ cycling contributes to triggered activity and arrhythmias in the heart. We investigated the properties and underlying mechanisms for systolic triggered Ca2+ waves in left atria from normal and failing dog hearts. Methods and results: Intracellular Ca2+ cycling was studied using confocal microscopy during rapid pacing of atrial myocytes (36 °C) isolated from normal and failing canine hearts (ventricular tachypacing model). In normal atrial myocytes (NAMs), Ca2+ waves developed during rapid pacing at rates ≥ 3.3 Hz and immediately disappeared upon cessation of pacing despite high sarcoplasmic reticulum (SR) load. In heart failure atrial myocytes (HFAMs), triggered Ca2+ waves (TCWs) developed at a higher incidence at slower rates. Because of their timing, TCW development relies upon action potential (AP)-evoked Ca2+ entry. The distribution of Ca2+ wave latencies indicated two populations of waves, with early events representing TCWs and late events representing conventional spontaneous Ca2+ waves. Latency analysis also demonstrated that TCWs arise after junctional Ca2+ release has occurred and spread to non-junctional (cell core) SR. TCWs also occurred in intact dog atrium and in myocytes from humans and pigs. ß-adrenergic stimulation increased Ca2+ release and abolished TCWs in NAMs but was ineffective in HFAMs making this a potentially effective adaptive mechanism in normals but potentially arrhythmogenic in HF. Block of Ca-calmodulin kinase II also abolished TCWs, suggesting a role in TCW formation. Pharmacological manoeuvres that increased Ca2+ release suppressed TCWs as did interventions that decreased Ca2+ release but these also severely reduced excitation-contraction coupling. Conclusion: TCWs develop during the atrial AP and thus could affect AP duration, producing repolarization gradients and creating a substrate for reentry, particularly in HF where they develop at slower rates and a higher incidence. TCWs may represent a mechanism for the initiation of atrial fibrillation particularly in HF.


Assuntos
Fibrilação Atrial/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Átrios do Coração/metabolismo , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , Potenciais de Ação , Animais , Antiarrítmicos/farmacologia , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/prevenção & controle , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Estimulação Cardíaca Artificial , Modelos Animais de Doenças , Cães , Acoplamento Excitação-Contração , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca , Humanos , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Sus scrofa , Fatores de Tempo
9.
Nat Commun ; 8(1): 106, 2017 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-28740174

RESUMO

Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell-cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for CaV1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease.It is believed that mutations in desmosomal adhesion complex protein plakophilin 2 (PKP2) cause arrhythmia due to loss of cell-cell communication. Here the authors show that PKP2 controls the expression of proteins involved in calcium cycling in adult mouse hearts, and that lack of PKP2 can cause arrhythmia in a structurally normal heart.


Assuntos
Cálcio/metabolismo , Coração/fisiologia , Miocárdio/metabolismo , Placofilinas/genética , Transcrição Genética , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Western Blotting , Expressão Gênica , Coração/fisiopatologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Miocárdio/citologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Placofilinas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
J Mol Cell Cardiol ; 103: 40-47, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28065668

RESUMO

BACKGROUND: Phosphorylation of the cardiac ryanodine receptor (RyR2) phospho-site S2808 has been touted by the Marks group as a hallmark of heart failure (HF) and a critical mediator of the physiological fight-or-flight response of the heart. In support of this hypothesis, mice unable to undergo phosphorylation at RyR2-S2808 (S2808A) were significantly protected against HF and displayed a blunted response to adrenergic stimulation. However, the issue remains highly controversial because several groups have been unable to reproduce these findings. An important variable not considered before is the genetic background of the mice used to obtain these divergent results. METHODS AND RESULTS: We backcrossed a RyR2-S2808A mouse into a congenic C57Bl/6 strain, the same strain used by the Marks group to conduct their experiments. We then performed several key experiments to confirm or discard the genetic background of the mouse as a relevant variable, including induction of HF by myocardial infarction and tests of integrity of adrenergic response. Congenic C57Bl/6 harboring the S2808A mutation showed similar echocardiographic parameters that indicated identical progression towards HF compared to wild type controls, and had a normal response to adrenergic stimulation in whole animal and cellular experiments. CONCLUSIONS: The genetic background of the different mouse models is unlikely to be the source of the divergent results obtained by the Marks group in comparison to several other groups. Cardiac adrenergic response and progression towards HF proceed unaltered in mice harboring the RyR2-S2808A mutation. Preventing RyR2-S2808 phosphorylation does not preclude a normal sympathetic response nor mitigates the pathophysiological consequences of MI.


Assuntos
Adrenérgicos/farmacologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Acoplamento Excitação-Contração/efeitos dos fármacos , Acoplamento Excitação-Contração/genética , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/patologia , Testes de Função Cardíaca , Camundongos , Camundongos Transgênicos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Fosforilação/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/deficiência , Análise de Sequência de DNA
11.
J Physiol ; 595(12): 4089-4108, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28105734

RESUMO

KEY POINTS: Spontaneous sarcoplasmic reticulum (SR) Ca2+ release events increased in fructose-rich diet mouse (FRD) myocytes vs. control diet (CD) mice, in the absence of significant changes in SR Ca2+ load. In HEK293 cells, hyperglycaemia significantly enhanced [3 H]ryanodine binding and Ca2+ /calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2-S2814 residue vs. normoglycaemia. These increases were prevented by CaMKII inhibition. FRD significantly augmented cardiac apoptosis in WT vs. CD-WT mice, which was prevented by co-treatment with the reactive oxygen species scavenger Tempol. Oxidative stress was also increased in FRD-SR-autocamide inhibitory peptide (AIP) mice, expressing the SR-targeted CaMKII inhibitor AIP, without any significant enhancement of apoptosis vs. CD-SR-AIP mice. FRD produced mitochondrial swelling and membrane depolarization in FRD-WT mice but not in FRD-S2814A mice, in which the CaMKII site on ryanodine receptor 2 was ablated. FRD decreased mitochondrial area, mean Feret diameter and the mean distance between SR and the outer mitochondrial membrane vs. CD hearts. This remodelling was prevented in AC3I mice, with cardiac-targeted CaMKII inhibition. ABSTRACT: The impact of cardiac apoptosis in pre-diabetic stages of diabetic cardiomyopathy is unknown. We show that myocytes from fructose-rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca2+ /calmodulin-protein kinase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca2+ leak. We tested the hypothesis that this mechanism also underlies cardiac apoptosis in pre-diabetes. We generated a pre-diabetic model in FRD mice. FRD mice showed an increase in oxidative stress, hypertrophy and systolic dysfunction. FRD myocytes exhibited enhanced SR Ca2+ spontaneous events in the absence of SR Ca2+ load alterations vs. control-diet (CD) myocytes. In HEK293 cells, hyperglycaemia significantly enhanced [3 H]ryanodine binding and CaMKII phosphorylation of RyR2-S2814 residue vs. normoglycaemia. CaMKII inhibition prevented hyperglycaemia-induced alterations. FRD also evoked cardiac apoptosis in WT mice vs. CD-WT mice. Co-treatment with the reactive oxygen species scavenger Tempol prevented FRD-induced apoptosis in WT mice. In contrast, FRD enhanced oxidative stress but not apoptosis in FRD-SR-AIP mice, in which a CaMKII inhibitor is targeted to the SR. FRD produced mitochondrial membrane depolarization in WT mice but not in S2814A mice, in which the CaMKII phosphorylation site on RyR2 was ablated. Furthermore, FRD decreased mitochondrial area, mean Feret diameter and mean SR-mitochondrial distance vs. CD-WT hearts. This remodelling was prevented in AC3I mice, with cardiac-targeted CaMKII inhibition. CaMKII phosphorylation of RyR2, SR Ca2+ leak and mitochondrial membrane depolarization are critically involved in the apoptotic pathway of the pre-diabetic heart. The FRD-induced decrease in SR-mitochondrial distance is likely to additionally favour Ca2+ transit between the two organelles.


Assuntos
Apoptose/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Calmodulina/metabolismo , Intolerância à Glucose/metabolismo , Transdução de Sinais/fisiologia , Animais , Arritmias Cardíacas/metabolismo , Sinalização do Cálcio/fisiologia , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatias/metabolismo , Linhagem Celular , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Retículo Sarcoplasmático/metabolismo
12.
Circulation ; 134(22): 1738-1748, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27688314

RESUMO

BACKGROUND: Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. METHODS: We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). RESULTS: Gene expression and protein levels for calsequestrin, L-type calcium channel, sodium-calcium exchanger, phospholamban, calcineurin, and calcium/calmodulin-dependent protein kinase type II (CaMKII) were similar in HCM samples compared with controls. CaMKII protein abundance was increased only in sarcomere-mutation HCM (P<0.001). The CaMKII target pT17-phospholamban was 5.5-fold increased only in sarcomere-mutation HCM (P=0.01), as was autophosphorylated CaMKII (P<0.01), suggestive of constitutive activation. Calcineurin (PPP3CB) mRNA was not increased, nor was RCAN1 mRNA level, indicating a lack of calcineurin activation. Furthermore, myocyte enhancer factor 2 and nuclear factor of activated T cell transcription factor activity was not increased in HCM, suggesting that calcineurin pathway activation is not an upstream cause of increased CAMKII protein abundance or activation. SERCA2A mRNA transcript levels were reduced in HCM regardless of genotype, as was sarcoplasmic endoplasmic reticular calcium ATPase 2/phospholamban protein ratio (45% reduced; P=0.03). 45Ca sarcoplasmic endoplasmic reticular calcium ATPaseuptake assay showed reduced uptake velocity in HCM regardless of genotype (P=0.01). The cardiac ryanodine receptor was not altered in transcript, protein, or phosphorylated (pS2808, pS2814) protein abundance, and [3H]ryanodine binding was not different in HCM, consistent with no major modification of the ryanodine receptor. CONCLUSIONS: Human HCM demonstrates calcium mishandling through both genotype-specific and common pathways. Posttranslational activation of the CaMKII pathway is specific to sarcomere mutation-positive HCM, whereas sarcoplasmic endoplasmic reticular calcium ATPase 2 abundance and sarcoplasmic reticulum Ca uptake are depressed in both sarcomere mutation-positive and -negative HCM.


Assuntos
Sinalização do Cálcio/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Regulação para Baixo , Expressão Gênica , Genótipo , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Sarcômeros/genética , Sarcômeros/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/biossíntese , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
13.
Artigo em Espanhol | PAHO | ID: pah-19724

RESUMO

Se determinó el efecto bactericida de los sebrenadantes de las soluciones saturadas de cal común y de hidróxido de calcio (Ca(OH)2) micronizado (1500 mg/L), que se usó a manera de testigo, comparándolo con el de los desinfectantes constituídos por soluciones de plata coloidal al 0,33 por ciento (0,0016mg/L), sulfacloramina de tolueno (41 mg/L) con bicarbonato de sodio (9 mg/L) e hipoclorito de sodio (5 mg/L). Para ello se emplearon cuatro cepas de Vibrio cholerae No. 01, V. parahaemolyticus, Escherichia coli, salmonella typhimurium, shigella flexneri, Sh. sonnei y Sa. enteritidis. Estas bacterias se usaron para inocular las sustancias bactericidas ya citadas y, después de distintos tiempos de incubación, las bacterias sobrevivientes se cuantificaron in vitro por medio de la técnica de vaciado en placa. El resultado se expresó en unidades formadoras de colonias (UFC). Se estimó in situ la carga de V. cholerae soltada por 35 fresas y 35 rábanos (con un peso aproximado de 10 g por unidad) al lavarlos bajo un chorro de agua potable, sumergirlos en el sobrenadantes de una solución saturada de cal (1,5 g/L), y ambas cosas. El mayor efecto bactericida se obtuvo con V. cholerae O1 y se observó a los 3 minutos. Otras enterobacterias resistieron el efecto bactericida hasta 30 minutos (AU)


Assuntos
Desinfetantes/análise , Bicarbonato de Sódio , Hidróxido de Cálcio
14.
Artigo | PAHO-IRIS | ID: phr-15600

RESUMO

Se determinó el efecto bactericida de los sebrenadantes de las soluciones saturadas de cal común y de hidróxido de calcio (Ca(OH)2) micronizado (1500 mg/L), que se usó a manera de testigo, comparándolo con el de los desinfectantes constituídos por soluciones de plata coloidal al 0,33 por ciento (0,0016mg/L), sulfacloramina de tolueno (41 mg/L) con bicarbonato de sodio (9 mg/L) e hipoclorito de sodio (5 mg/L). Para ello se emplearon cuatro cepas de Vibrio cholerae No. 01, V. parahaemolyticus, Escherichia coli, salmonella typhimurium, shigella flexneri, Sh. sonnei y Sa. enteritidis. Estas bacterias se usaron para inocular las sustancias bactericidas ya citadas y, después de distintos tiempos de incubación, las bacterias sobrevivientes se cuantificaron in vitro por medio de la técnica de vaciado en placa. El resultado se expresó en unidades formadoras de colonias (UFC). Se estimó in situ la carga de V. cholerae soltada por 35 fresas y 35 rábanos (con un peso aproximado de 10 g por unidad) al lavarlos bajo un chorro de agua potable, sumergirlos en el sobrenadantes de una solución saturada de cal (1,5 g/L), y ambas cosas. El mayor efecto bactericida se obtuvo con V. cholerae O1 y se observó a los 3 minutos. Otras enterobacterias resistieron el efecto bactericida hasta 30 minutos (AU)


Assuntos
Desinfetantes , Bicarbonato de Sódio , Hidróxido de Cálcio
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