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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2022: 910-913, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36086113

RESUMO

We present the development of novel tetrapolar EIS biosensor for the detect of troponin. Troponin has considerable diagnostic power and provide invaluable prognostic information for risk stratification. of acute coronary syndromes. Clinical Relevance- A feasibility study was undertaken to assess the diagnostic performance of serial cardiac troponin measurements which is excellent as these structural proteins are unique to the heart and thus sensitive and specific of damage to the myocardium. clinical molecular diagnostics and home healthcare. Troponin's biosensors would provide point-of-care and rapid decision making for the early detection of CS. Clinically relevant window of cTnI testing, concentrations from 10pM to 0.1µM were achieved.


Assuntos
Técnicas Biossensoriais , Sistemas Automatizados de Assistência Junto ao Leito , Biomarcadores/análise , Testes Hematológicos , Troponina I/análise , Troponina I/metabolismo
2.
Rev Assoc Med Bras (1992) ; 68(8): 1011-1016, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36134829

RESUMO

OBJECTIVE: Heart attack is one of the most common causes of sudden death in adults. Therefore, early detection of heart attack and investigation of potential new biomarkers are of great importance. We investigated whether perilipin-5 is a potential biomarker by examining changes in perilipin-5 serum levels along with high-sensitivity cardiac troponin I during a heart attack. METHODS: The subjects were divided into two groups: (1) control group and (2) patients with heart attack, with 150 people in each group. High-sensitivity cardiac troponin I, perilipin-5, total oxidant status, malondialdehyde, reduced glutathione, and superoxide dismutase levels in serum samples were measured. In addition, perilipin-5 mRNA expressions and protein levels were analyzed. RESULTS: There was no overall statistical difference between the demographic characteristics of the groups. However, high-density lipoprotein, creatine kinase, Creatine kinase myocardial band, aspartate amino transferase, lactate dehydrogenase, and calcium levels were higher in the heart attack group compared to the control group. We found that the high-sensitivity cardiac troponin I and perilipin-5 levels increased in the patients with heart attack (p<0.0001) compared to control. Although there was an insignificant increase in malondialdehyde levels in the heart attack group (p>0.05), there was a 35.9% increase in total oxidant status levels and a 33.5 and 24.1% decrease in glutathione and superoxide dismutase levels, respectively (p<0.01), compared to control. Perilipin-5 mRNA and protein levels in heart attack patients increased by 48.2 and 23.6%, respectively, compared to the control group (p<0.01). CONCLUSION: Our results showed that perilipin-5 together with high-sensitivity cardiac troponin I could be a promising biomarker in heart attack.


Assuntos
Infarto do Miocárdio , Troponina I , Adulto , Ácido Aspártico/metabolismo , Biomarcadores , Cálcio/metabolismo , Creatina/metabolismo , Creatina Quinase/metabolismo , Glutationa , Humanos , L-Lactato Desidrogenase , Metabolismo dos Lipídeos , Lipoproteínas HDL , Malondialdeído , Oxidantes , Perilipina-5/metabolismo , RNA Mensageiro/metabolismo , Superóxido Dismutase , Troponina I/metabolismo
3.
Biomolecules ; 12(9)2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36139129

RESUMO

The present study investigated whether Rho-associated protein kinase (RhoA/ROCK) signaling pathway inhibitor simvastatin inhibits matrix metalloproteinase 2 (MMP-2) activity in a rat ischemia-reperfusion injury (I/Ri) model by inhibiting the RhoA/ROCK pathway and reducing MMP-2 mRNA levels. Isolated rat hearts were subjected to aerobic perfusion or I/Ri control. The effect of simvastatin was assessed in hearts subjected to I/Ri. We determined cardiac mechanical function, the content of RhoA, phosphorylated myosin light chain subunit 1 (phospho-MYL9), troponin I, MMP-2, and MMP-2 mRNA in the heart homogenates, as well as MMP-2 activity in heart tissue. We showed that treatment with simvastatin caused improvement in the contractile function of the heart subjected to I/Ri which was accompanied by a decrease of MMP-2 activity in heart tissue along with inhibition of RhoA pathway, expressed in a reduction in both RhoA and its downstream product-phosphorylated myosin light chain (phospho-MYL9) in hearts treated with simvastatin. MMP-2 inactivation is not due to inhibition of MMP-2 m-RNA synthesis caused by inhibition of RhoA/ROCK pathway and is due, at least in part, to the direct drug action. The protective effect of simvastatin on systolic function in the acute ischemia-reperfusion model does not appear to be related to reduced MMP-2 activation, but other mechanisms related with the inhibition RhoA/ROCK pathway.


Assuntos
Metaloproteinase 2 da Matriz , Traumatismo por Reperfusão , Sinvastatina , Quinases Associadas a rho , Animais , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Cadeias Leves de Miosina/metabolismo , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Sinvastatina/farmacologia , Troponina I/metabolismo , Proteínas rho de Ligação ao GTP , Quinases Associadas a rho/metabolismo
4.
Biosensors (Basel) ; 12(7)2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35884242

RESUMO

Quantitative detection of cardiac troponin biomarkers in blood is an important method for clinical diagnosis of acute myocardial infarction (AMI). In this work, a whispering gallery mode (WGM) microcavity immunosensor based on a prefab hollow glass microsphere (HGMS) with liquid crystal (LC) sensitization was proposed and experimentally demonstrated for label-free cardiac troponin I-C (cTnI-C) complex detection. The proposed fiber-optic immunosensor has a simple structure; the tiny modified HGMS serves as the key sensing element and the microsample reservoir simultaneously. A sensitive LC layer with cTnI-C recognition ability was deposited on the inner wall of the HGMS microcavity. The arrangement of LC molecules is affected by the cTnI-C antigen-antibody binding in the HGMS, and the small change of the surface refractive index caused by the binding can be amplified owing to the birefringence property of LC. Using the annular waveguide of the HGMS, the WGMs were easily excited by the coupling scanning laser with a microfiber, and an all-fiber cTnI-C immunosensor can be achieved by measuring the resonant wavelength shift of the WGM spectrum. Moreover, the dynamic processes of the cTnI-C antigen-antibody binding and unbinding was revealed by monitoring the wavelength shift continuously. The proposed immunosensor with a spherical microcavity can be a cost-effective tool for AMI diagnosis.


Assuntos
Técnicas Biossensoriais , Cristais Líquidos , Infarto do Miocárdio , Biomarcadores , Técnicas Biossensoriais/métodos , Humanos , Imunoensaio/métodos , Microesferas , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Troponina I/metabolismo
5.
J Biochem Mol Toxicol ; 36(9): e23143, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35815753

RESUMO

Bergapten (BeG) is explored for its anti-inflammatory and antioxidant properties. Myocardial infarction (MI) is reported to be one of the leading cardiovascular diseases characterized by mitochondrial dysfunction and apoptosis. The main purpose of this study is to assess the cardiopreventive effects of BeG (50 mg/kg) in isoproterenol (ISO)-induced MI in Wistar rats. The increased infarct size after ISO induction was reduced simultaneously on treatment with BeG. Similarly, augmented levels of cardiac biomarkers, namely cardiac troponin T, creatine kinase (CK), cardiac troponin I, and CK-MB were also suppressed by BeG. The increased rate of lipid hydroperoxides and thiobarbituric acid reactive substances owing to the oxidative stress caused by free radical generation in ISO-induced rats were also inhibited by BeG. Antioxidants reduce oxidative stress by scavenging free radicals. ISO induction reduces these antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase, and glutathione, and levels causing oxidative cardiac damage to the heart tissue. BeG supplementation improved these enzymes synthesis preventing potential damage to the myocardium. Inflammation caused by ISO pretreatment increased the secretion of proinflammatory cytokines in ISO-induced rats. Pretreatment with BeG suppressed these inflammatory cytokines to a normal level in ISO + BeG-treated rats. The histopathological examination of the morphological characteristics showed that the intensity of cardiac damage caused by ISO induction was less in BeG pretreated rats with less inflammatory cells and no necrosis. BeG also showed promising results in the molecular alteration of AMP-activated protein kinase/endothelial nitric oxide synthase/protein kinase B signaling molecules. These observations emphasize the cardioprotective effects of BeG and its potential use as a drug in the near future.


Assuntos
Proteínas Quinases Ativadas por AMP , Infarto do Miocárdio , 5-Metoxipsoraleno/efeitos adversos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose , Biomarcadores/metabolismo , Catalase/metabolismo , Creatina Quinase Forma MB , Citocinas/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Isoproterenol/toxicidade , Peróxidos Lipídicos/metabolismo , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Troponina I/efeitos adversos , Troponina I/metabolismo , Troponina T/metabolismo , Troponina T/farmacologia
6.
Clin Exp Pharmacol Physiol ; 49(11): 1169-1178, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35781726

RESUMO

Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase that has been identified as a diagnostic marker and a therapeutic target in cardiovascular diseases. However, the biological function of TNNI3K in cardiac dysfunction and remodelling remains elusive. In the present study, a Tnni3k cardiomyocyte-specific knockout (Tnni3k-cKO) mouse model was established. Echocardiography was used to evaluate cardiac function in mice. Heart failure markers were detected using enzyme-linked immunosorbent assay. Haematoxylin and eosin staining, wheat germ agglutinin staining, Masson's trichrome staining, Sirius red staining and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining were used to assess histopathological changes, cardiac hypertrophy, collagen deposition and myocardial apoptosis, respectively. Expression levels of TNNI3K, apoptosis-related proteins, and p38 mitogen-activated protein kinase were measured using Western blot analysis. Compared to wild-type controls, cardiac dysfunction and cardiac remodelling of Tnni3k-cKO mice increased gradually with age. Tnni3k-cKO mice exhibited cardiac hypertrophy, cardiac fibrosis and cardiomyocyte apoptosis. Upregulation of cleaved caspase-3 in Tnni3k-cKO mice appeared to be related to phosphorylation and activation of the p38 mitogen-activated protein kinase signalling pathway. In conclusion, this study shows that TNNI3K is essential for cardiac development and function, providing new insights into the development of novel therapeutic strategies for cardiac diseases.


Assuntos
Cardiopatias , Troponina I , Animais , Apoptose , Cardiomegalia/metabolismo , Caspase 3/metabolismo , DNA Nucleotidilexotransferase/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Cardiopatias/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases , Troponina I/metabolismo , Aglutininas do Germe de Trigo/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Exp Physiol ; 107(10): 1159-1171, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35654394

RESUMO

NEW FINDINGS: What is the topic of this review? The status and potential role of novel biological markers (biomarkers) that can help identify the patients at risk of organ injury or long-term complications following heatstroke. What advances does it highlight? Numerous biomarkers were identified related to many aspects of generalized heatstroke-induced cellular injury and tissue damage, and heatstroke-provoked cardiovascular, renal, cerebral, intestinal and skeletal muscle injury. No novel biomarkers were identified for liver or lung injury. ABSTRACT: Classic and exertional heatstroke cause acute injury and damage across numerous organ systems. Moreover, heatstroke survivors may sustain long-term neurological, cardiovascular and renal complications with a persistent risk of death. In this context, biomarkers, defined as biological samples obtained from heatstroke patients, are needed to detect early organ injury, and predict outcomes to develop novel organ preservation therapeutic strategies. This narrative review provides preliminary insights that will guide the development and future utilization of these biomarkers. To this end, we have identified numerous biomarkers of widespread heatstroke-associated cellular injury, tissue damage and repair (extracellular heat shock proteins 72 and 60, high mobility group box protein 1, histone H3, and interleukin-1α), and other organ-specific biomarkers including those related to the cardiovascular system (cardiac troponin I, endothelium-derived factors, circulation endothelial cells, adhesion molecules, thrombomodulin and von Willebrand factor antigen), the kidneys (plasma and urinary neutrophil gelatinase-associated lipocalin), the intestines (intestinal fatty acid-binding protein 2), the brain (serum S100ß and neuron-specific enolase) and skeletal muscle (creatine kinase, myoglobin). No specific biomarkers have been identified so far for liver or lung injury in heatstroke. Before translating the identified biomarkers into clinical practice, additional preclinical and clinical prospective studies are required to further understand their clinical utility, particularly for the biomarkers related to long-term post-heatstroke health outcomes.


Assuntos
Golpe de Calor , Lesão Pulmonar , Biomarcadores , Creatina Quinase/metabolismo , Células Endoteliais/metabolismo , Proteínas de Ligação a Ácido Graxo/uso terapêutico , Proteínas HMGB/metabolismo , Proteínas de Choque Térmico HSP72/metabolismo , Histonas , Humanos , Interleucina-1alfa/metabolismo , Lipocalina-2/uso terapêutico , Lesão Pulmonar/complicações , Mioglobina/metabolismo , Fosfopiruvato Hidratase/metabolismo , Trombomodulina/metabolismo , Trombomodulina/uso terapêutico , Troponina I/metabolismo , Fator de von Willebrand/metabolismo , Fator de von Willebrand/uso terapêutico
8.
Environ Sci Pollut Res Int ; 29(46): 69635-69651, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35576032

RESUMO

Cyclophosphamide (Cyclo) is a chemotherapeutic agent used as an immunosuppressant and as a treatment for many cancerous diseases. Many previous pieces of literature proved the marked cardio and neurotoxicity of the drug. Thus, this research provides evidence on the alleviative effect of flavocoxid on the cardiac and brain toxicity of cyclophosphamide in mice and determines its underlying mechanisms. Flavocoxid (Flavo) is a potent antioxidant and anti-inflammatory agent that inhibits the peroxidase activity of cyclooxygenase (COX-1 and COX-2) enzymes and 5-lipooxygenase (5-LOX). Flavo was administered orally (20 mg/kg) for 2 weeks, followed by Cyclo (100 mg/kg, i.p.) on day 14. Higher heart and brain weight indices, serum lactate dehydrogenase (LDH), creatine kinase (CK-MB), and nitric oxide (NO) were mitigated following Flavo administration. Flavo modulated oxidative stress biomarkers (malonaldehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD)), tumor necrosis factor-α (TNF-α), and interleukin (IL)-1ß. Additionally, cardiac troponin I (cTn-I), nuclear factor kappa B (NF-κB), brain amyloid precursor protein (APP), and granulocyte macrophage colony-stimulating factor (GM-CSF) were decreased by Flavo administration. Moreover, Flavo ameliorated heart and brain histopathological changes and caspase-3 levels. Collectively, Flavo (20 mg/kg) for 14 days showed significant cardio and neuroprotective effects due to its antioxidant, anti-inflammatory, and antiapoptotic activities via modulation of oxidative stress, inflammation, and the GM-CSF/NF-κB signaling pathway.


Assuntos
NF-kappa B , Fármacos Neuroprotetores , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Caspase 3/metabolismo , Catequina , Creatina Quinase/metabolismo , Creatina Quinase/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ciclofosfamida/toxicidade , Combinação de Medicamentos , Glutationa/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Imunossupressores/farmacologia , Interleucinas/metabolismo , Lactato Desidrogenases/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Malondialdeído/farmacologia , Camundongos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/farmacologia , Estresse Oxidativo , Peroxidases/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo , Troponina I/metabolismo , Troponina I/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
9.
J Phys Chem B ; 126(21): 3844-3851, 2022 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-35584206

RESUMO

The troponin core is an important regulatory complex in cardiac sarcomeres. Contraction is initiated by a calcium ion binding to cardiac troponin C (cTnC), initiating a conformational shift within the protein, altering its interactions with cardiac troponin I (cTnI). The change in cTnC-cTnI interactions prompts the C-terminal domain of cTnI to dissociate from actin, allowing tropomyosin to reveal myosin-binding sites on actin. Each of the concerted movements in the cardiac thin filament (CTF) is crucial for allowing the contraction of cardiomyocytes, yet little is known about the free energy associated with each transition, which is vital for understanding contraction on a molecular level. Using metadynamics, we calculated the free-energy surface of two transitions in the CTF: cTnC opening in the presence and absence of Ca2+ and cTnI dissociating from actin with both open and closed cTnC. These results not only provide the free-energy surface of the transitions but will also be shown to determine if the order of transitions in the contraction cycle is important. From our calculations, we found that the calcium ion helps stabilize the open conformation of cTnC and that the C-terminus of cTnI is stabilized by cTnC in the open conformation when dissociating from the actin surface.


Assuntos
Sarcômeros , Troponina C , Actinas/metabolismo , Cálcio/química , Contração Muscular , Miocárdio/metabolismo , Sarcômeros/metabolismo , Troponina C/química , Troponina I/metabolismo
10.
Am J Physiol Heart Circ Physiol ; 323(1): H1-H15, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35559722

RESUMO

Troponin released from irreversibly injured myocytes is the gold standard biomarker for the rapid identification of an acute coronary syndrome. In acute myocardial infarction, necrotic cell death is characterized by sarcolemmal disruption in response to a critical level of energy depletion after more than 15 min of ischemia. Although troponin I and T are highly specific for cardiomyocyte death, high-sensitivity assays have demonstrated that measurable circulating levels of troponin are present in many normal subjects. In addition, transient as well as chronic elevations have been demonstrated in many disease states not clearly associated with myocardial ischemia. The latter observations have given rise to the clinical concept of myocardial injury. This review will summarize evidence supporting the notion that circulating troponin levels parallel the extent of myocyte apoptosis in normal ventricular remodeling and in pathophysiological conditions not associated with infarction or necrosis. It will review the evidence that myocyte apoptosis can be accelerated by diastolic strain from elevated ventricular preload and systolic strain from dyskinesis after brief episodes of ischemia too short to cause a critical level of myocyte energy depletion. We then show how chronic, low rates of myocyte apoptosis from endogenous myocyte turnover, repetitive ischemia, or repetitive elevations in left ventricular diastolic pressure can lead to significant myocyte loss in the absence of neurohormonal stimulation. Finally, we posit that the differential response to strain-induced injury in heart failure may determine whether progressive myocyte loss and heart failure with reduced ejection fraction or interstitial fibrosis and heart failure with preserved ejection fraction become the heart failure phenotype.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Humanos , Miócitos Cardíacos/metabolismo , Necrose/metabolismo , Troponina I/metabolismo , Remodelação Ventricular
11.
Int J Mol Sci ; 23(9)2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35562865

RESUMO

Express and highly sensitive immunoassays for the quantitative registration of cardiac troponin I (cTnI) are in high demand for early point-of-care differential diagnosis of acute myocardial infarction. The selection of antibodies that feature rapid and tight binding with antigens is crucial for immunoassay rate and sensitivity. A method is presented for the selection of the most promising clones for advanced immunoassays via simultaneous characterization of interaction kinetics of different monoclonal antibodies (mAb) using a direct label-free method of multiplex spectral correlation interferometry. mAb-cTnI interactions were real-time registered on an epoxy-modified microarray glass sensor chip that did not require activation. The covalent immobilization of mAb microdots on its surface provided versatility, convenience, and virtually unlimited multiplexing potential. The kinetics of tracer antibody interaction with the "cTnI-capture antibody" complex was characterized. Algorithms are shown for excluding mutual competition of the tracer/capture antibodies and selecting the optimal pairs for different assay formats. Using the selected mAbs, a lateral flow assay was developed for rapid quantitative cTnI determination based on electronic detection of functionalized magnetic nanoparticles applied as labels (detection limit-0.08 ng/mL, dynamic range > 3 orders). The method can be extended to other molecular biomarkers for high-throughput screening of mAbs and rational development of immunoassays.


Assuntos
Infarto do Miocárdio , Troponina I , Anticorpos Monoclonais , Humanos , Imunoensaio/métodos , Cinética , Fenômenos Magnéticos , Infarto do Miocárdio/diagnóstico , Troponina I/metabolismo
12.
Circulation ; 145(24): 1764-1779, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35389756

RESUMO

BACKGROUND: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). METHODS: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. RESULTS: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, PWald<0.001); the expression correlated with pathological disease activity (R=0.59, Pt-statistic<0.001) and circulating hs-cTnT concentrations (R=0.26, Pt-statistic=0.031). CONCLUSIONS: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03660969.


Assuntos
Cardiopatias/metabolismo , Doenças Musculares/metabolismo , Troponina I/metabolismo , Troponina T/metabolismo , Biomarcadores , Estudos de Casos e Controles , Feminino , Cardiopatias/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Estudos Prospectivos , RNA Mensageiro/análise , Reprodutibilidade dos Testes , Troponina I/genética , Troponina T/genética
13.
J Appl Physiol (1985) ; 132(6): 1350-1360, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35482324

RESUMO

The cardiovascular benefits of regular exercise are unequivocal, yet patients with type 2 diabetes respond poorly to exercise due to a reduced cardiac reserve. The contractile response of diabetic cardiomyocytes to ß-adrenergic stimulation is attenuated, which may result in altered myofilament calcium sensitivity and posttranslational modifications of cardiac troponin I (cTnI). Treadmill running increases myofilament calcium sensitivity in nondiabetic rats, and thus we hypothesized that endurance training would increase calcium sensitivity of diabetic cardiomyocytes and alter site-specific phosphorylation of cTnI. Calcium sensitivity, or pCa50, was measured in Zucker diabetic fatty (ZDF), nondiabetic (nDM), and diabetic (DM) rat hearts after 8 wk of either a sedentary (SED) or progressive treadmill running (TR) intervention. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca2+]). Specific phospho-sites on cTnI and O-GlcNAcylation were quantified by immunoblot and total protein phosphorylation by fluorescent gel staining (ProQ Diamond). The novel finding in this study was that training increased pCa50 in both DM and nDM cardiomyocytes (P = 0.009). Phosphorylation of cTnI amino acid residues Ser23/24, a crucial protein kinase A site, and Threonine (Thr)144 was lower in DM hearts, but there was no effect of training on site-specific phosphorylation. In addition, total phosphorylation and O-GlcNAcylation levels were not different between SED and TR groups. These findings suggest that regular exercise may benefit the diabetic heart by specifically targeting myofilament contractile function.NEW & NOTEWORTHY We examined the effects of training on the myofilament calcium in diabetic rat hearts. After 8 wk of treadmill running, both nondiabetic and diabetic cardiomyocytes had increased myofilament calcium sensitivity compared with their sedentary counterparts, but there was no effect of training on the phosphorylation or O-GlcNAcylation status of myofilament proteins measured in this study. These data highlight one potential mechanism capable of reversing, in part, reduced cardiac reserve in the diabetic heart.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Corrida , Animais , Cálcio/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Miofibrilas/metabolismo , Fosforilação , Ratos , Ratos Zucker , Troponina I/metabolismo
14.
Mol Pharmacol ; 101(5): 286-299, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35236770

RESUMO

We tested the hypothesis that isoform shifts in sarcomeres of the immature heart modify the effect of cardiac myosin-directed sarcomere inhibitors and activators. Omecamtiv mecarbil (OM) activates tension and is in clinical trials for the treatment of adult acute and chronic heart failure. Mavacamten (Mava) inhibits tension and is in clinical trials to relieve hypercontractility and outflow obstruction in advanced genetic hypertrophic cardiomyopathy (HCM), which is often linked to mutations in sarcomeric proteins. To address the effect of these agents in developing sarcomeres, we isolated heart fiber bundles, extracted membranes with Triton X-100, and measured tension developed over a range of Ca2+ concentrations with and without OM or Mava treatment. We made measurements in fiber bundles from hearts of adult nontransgenic (NTG) controls expressing cardiac troponin I (cTnI), and from hearts of transgenic (TG-ssTnI) mice expressing the fetal/neonatal form, slow skeletal troponin I (ssTnI). We also compared fibers from 7- and 14-day-old NTG mice expressing ssTnI and cTnI. These studies were repeated with 7- and 14-day-old transgenic mice (TG-cTnT-R92Q) expressing a mutant form of cardiac troponin T (cTnT) linked to HCM. OM increased Ca2+-sensitivity and decreased cooperative activation in both ssTnI- and cTnI-regulated myofilaments with a similar effect: reducing submaximal tension in immature and mature myofilaments. Although Mava decreased tension similarly in cTnI- and ssTnI-regulated myofilaments controlled either by cTnT or cTnT-R92Q, its effect involved a depressed Ca2+-sensitivity in the mature cTnT-R92 myofilaments. Our data demonstrate an influence of myosin and thin-filament associated proteins on the actions of myosin-directed agents such as OM and Mava. SIGNIFICANCE STATEMENT: The effects of myosin-targeted activators and inhibitors on Ca2+-activated tension in developing cardiac sarcomeres presented here provide novel, ex vivo evidence as to their actions in early-stage cardiac disorders. These studies advance understanding of the molecular mechanisms of these agents, which are important in preclinical studies employing sarcomere Ca2+-response as a screening approach. The data also inform the use of commonly immature cardiac myocytes generated from human-inducible pluripotent stem cells in screening for sarcomere activators and inhibitors.


Assuntos
Miofibrilas , Sarcômeros , Animais , Cálcio/metabolismo , Camundongos , Camundongos Transgênicos , Contração Miocárdica , Miocárdio/metabolismo , Miócitos Cardíacos , Miofibrilas/metabolismo , Miosinas/metabolismo , Miosinas/farmacologia , Troponina I/genética , Troponina I/metabolismo , Troponina I/farmacologia
15.
Mol Cell Biochem ; 477(6): 1803-1815, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35316461

RESUMO

The cardiac isoform of troponin I has a unique N-terminal extension (~ 1-30 amino acids), which contributes to the modulation of cardiac contraction and relaxation. Hearts of various species including humans produce a truncated variant of cardiac troponin I (cTnI-ND) deleting the first ~ 30 amino acids as an adaption in pathophysiological conditions. In this study, we investigated the impact of cTnI-ND chronic expression in transgenic mouse hearts compared to wildtype (WT) controls (biological n = 8 in each group). We aimed to determine the global phosphorylation effects of cTnI-ND on the cardiac proteome, thereby determining the signaling pathways that have an impact on cardiac function. The samples were digested and isobarically labeled and equally mixed for relative quantification via nanoLC-MS/MS. The peptides were then enriched for phospho-peptides and bioinformatic analysis was done with Ingenuity Pathway Analysis (IPA). We found approximately 77% replacement of the endogenous intact cTnI with cTnI-ND in the transgenic mouse hearts with 1674 phospho-proteins and 2971 non-modified proteins. There were 73 significantly altered phospho-proteins; bioinformatic analysis identified the top canonical pathways as associated with integrin, protein kinase A, RhoA, and actin cytoskeleton signaling. Among the 73 phospho-proteins compared to controls cTnI-ND hearts demonstrated a significant decrease in paxillin and YAP1, which are known to play a role in cell mechano-sensing pathways. Our data indicate that cTnI-ND modifications in the sarcomere are sufficient to initiate changes in the phospho-signaling profile that may underly the chronic-adaptive response associated with cTnI cleavage in response to stressors by modifying mechano-sensitive signaling pathways.


Assuntos
Espectrometria de Massas em Tandem , Troponina I , Aminoácidos , Animais , Cálcio/metabolismo , Camundongos , Camundongos Transgênicos , Contração Miocárdica , Miocárdio/metabolismo , Peptídeos , Fosforilação , Transdução de Sinais , Troponina I/química , Troponina I/genética , Troponina I/metabolismo
16.
Scand J Clin Lab Invest ; 82(2): 104-107, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35112632

RESUMO

Chronic elevation of cardiac troponin I (cTnI) is associated with heart failure and cardiovascular death. Paradoxically, observational studies have indicated that current smokers have lower cTnI concentrations than non-smokers. We examined determinants of cTnI in smokers and the effect of smoking cessation on cTnI. Overweight or obese smokers received motivational support and varenicline to aid cessation and dietary advice to limit weight gain. Quitters were defined according to the Russell standard (≤5 cigarettes after the quit date) and validated with expired breath CO <10 ppm. Of the total 122 participants, 108 completed assessments at 12 weeks and 78 were classified as quitters versus 30 who continued smoking. cTnI was measured with a high-sensitivity assay with a limit of detection of 1.2 ng/L (Abbott Diagnostics), and concentrations (log-transformed) were compared between quitters and continuing smokers. cTnI concentrations were significantly higher in men than women and correlated with age, but not with number of cigarettes/day. Quitters had median baseline and 12-week levels of 1.4 ng/L (interquartile range [IQR] 1.2-2.5) and 1.4 ng/L (IQR 1.2-2.4), respectively, while nonquitters had baseline and 12-week levels of 1.5 ng/L (IQR 1.2-2.9) and 1.8 ng/L (IQR 1.3-3.4), respectively. The change in cTnI concentrations from baseline to 12 weeks did not differ between quitters and continuous smokers (p = .7). The results suggest that smoking cessation does not affect levels of cTnI, a marker of chronic subclinical myocardial injury, in contrast to prior observational data suggesting that tobacco smoking is associated with lower cTn concentrations.


Assuntos
Insuficiência Cardíaca , Abandono do Hábito de Fumar , Troponina I , Biomarcadores , Feminino , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Estudos Observacionais como Assunto , Fumar/metabolismo , Troponina I/metabolismo
17.
EBioMedicine ; 76: 103821, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35144887

RESUMO

BACKGROUND: Although acute cardiac injury (ACI) is a known COVID-19 complication, whether ACI acquired during COVID-19 recovers is unknown. This study investigated the incidence of persistent ACI and identified clinical predictors of ACI recovery in hospitalized patients with COVID-19 2.5 months post-discharge. METHODS: This retrospective study consisted of 10,696 hospitalized COVID-19 patients from March 11, 2020 to June 3, 2021. Demographics, comorbidities, and laboratory tests were collected at ACI onset, hospital discharge, and 2.5 months post-discharge. ACI was defined as serum troponin-T (TNT) level >99th-percentile upper reference limit (0.014ng/mL) during hospitalization, and recovery was defined as TNT below this threshold 2.5 months post-discharge. Four models were used to predict ACI recovery status. RESULTS: There were 4,248 (39.7%) COVID-19 patients with ACI, with most (93%) developed ACI on or within a day after admission. In-hospital mortality odds ratio of ACI patients was 4.45 [95%CI: 3.92, 5.05, p<0.001] compared to non-ACI patients. Of the 2,880 ACI survivors, 1,114 (38.7%) returned to our hospitals 2.5 months on average post-discharge, of which only 302 (44.9%) out of 673 patients recovered from ACI. There were no significant differences in demographics, race, ethnicity, major commodities, and length of hospital stay between groups. Prediction of ACI recovery post-discharge using the top predictors (troponin, creatinine, lymphocyte, sodium, lactate dehydrogenase, lymphocytes and hematocrit) at discharge yielded 63.73%-75.73% accuracy. INTERPRETATION: Persistent cardiac injury is common among COVID-19 survivors. Readily available patient data accurately predict ACI recovery post-discharge. Early identification of at-risk patients could help prevent long-term cardiovascular complications. FUNDING: None.


Assuntos
COVID-19/patologia , Traumatismos Cardíacos/diagnóstico , Troponina I/metabolismo , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , COVID-19/virologia , Feminino , Traumatismos Cardíacos/epidemiologia , Traumatismos Cardíacos/etiologia , Traumatismos Cardíacos/mortalidade , Mortalidade Hospitalar , Humanos , Incidência , L-Lactato Desidrogenase/metabolismo , Modelos Logísticos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , New York/epidemiologia , Alta do Paciente , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação
18.
Cell Mol Life Sci ; 79(2): 84, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35059851

RESUMO

The release of extracellular vesicles (EVs) is increased under cellular stress and cardiomyocyte damaging conditions. However, whether the cardiomyocyte-derived EVs eventually reach the systemic circulation and whether their number in the bloodstream reflects cardiac injury, remains unknown. Wild type C57B/6 and conditional transgenic mice expressing green fluorescent protein (GFP) by cardiomyocytes were studied in lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome (SIRS). EVs were separated both from platelet-free plasma and from the conditioned medium of isolated cardiomyocytes of the left ventricular wall. Size distribution and concentration of the released particles were determined by Nanoparticle Tracking Analysis. The presence of GFP + cardiomyocyte-derived circulating EVs was monitored by flow cytometry and cardiac function was assessed by echocardiography. In LPS-treated mice, systemic inflammation and the consequent cardiomyopathy were verified by elevated plasma levels of TNFα, GDF-15, and cardiac troponin I, and by a decrease in the ejection fraction. Furthermore, we demonstrated elevated levels of circulating small- and medium-sized EVs in the LPS-injected mice. Importantly, we detected GFP+ cardiomyocyte-derived EVs in the circulation of control mice, and the number of these circulating GFP+ vesicles increased significantly upon intraperitoneal LPS administration (P = 0.029). The cardiomyocyte-derived GFP+ EVs were also positive for intravesicular troponin I (cTnI) and muscle-associated glycogen phosphorylase (PYGM). This is the first direct demonstration that cardiomyocyte-derived EVs are present in the circulation and that the increased number of cardiac-derived EVs in the blood reflects cardiac injury in LPS-induced systemic inflammation (SIRS).


Assuntos
Movimento Celular , Vesículas Extracelulares/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/patologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Animais , Movimento Celular/efeitos dos fármacos , Clusterina/metabolismo , Vesículas Extracelulares/efeitos dos fármacos , Glicogênio Fosforilase/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Integrases/metabolismo , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Especificidade de Órgãos/efeitos dos fármacos , Fenótipo , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Tamoxifeno/farmacologia , Troponina I/metabolismo
19.
Cell Mol Life Sci ; 79(1): 71, 2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35029764

RESUMO

In the cartilage matrix, complex interactions occur between angiogenic and anti-angiogenic components, growth factors, and environmental stressors to maintain a proper cartilage phenotype that allows for effective load bearing and force distribution. However, as seen in both degenerative disease and tissue engineering, cartilage can lose its vascular resistance. This vascularization then leads to matrix breakdown, chondrocyte apoptosis, and ossification. Research has shown that articular cartilage inflammation leads to compromised joint function and decreased clinical potential for regeneration. Unfortunately, few articles comprehensively summarize what we have learned from previous investigations. In this review, we summarize our current understanding of the factors that stabilize chondrocytes to prevent terminal differentiation and applications of these factors to rescue the cartilage phenotype during cartilage engineering and osteoarthritis treatment. Inhibiting vascularization will allow for enhanced phenotypic stability so that we are able to develop more stable implants for cartilage repair and regeneration.


Assuntos
Inibidores da Angiogênese/farmacologia , Cartilagem/patologia , Cartilagem/fisiopatologia , Osteoartrite/terapia , Engenharia Tecidual/métodos , Agrecanas/metabolismo , Angiostatinas/metabolismo , Animais , Apoptose , Condrócitos/patologia , Citocinas/metabolismo , Endostatinas/metabolismo , Humanos , Inflamação , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos , Osteogênese , Regeneração , Inibidores de Serino Proteinase/química , Células-Tronco/patologia , Trombospondinas/metabolismo , Extratos de Tecidos/metabolismo , Troponina I/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
20.
Sci Rep ; 12(1): 945, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35042885

RESUMO

To compare the performance of high-sensitivity cardiac troponin I and T (hs-cTnI; hs-cTnT) in diagnosing obstructive coronary artery disease (CAD50) in patients with suspected chronic coronary syndrome (CCS). A total of 706 patients with suspected CCS, referred for Coronary Computed Tomography Angiography, were included. cTn concentrations were measured using the Singulex hs-cTnI (limit of detection [LoD] 0.08 ng/L) and Roche hs-cTnT (LoD 3 ng/L) assays. Obstructive coronary artery disease (CAD50) was defined as ≥ 50% coronary stenosis. Cardiovascular risk was determined by the NORRISK2-score. Median age of the patients was 65 (range 28-87) years, 35% were women. All patients had hs-cTnI concentrations above the LoD (median 1.9 [Q1-3 1.2-3.6] ng/L), 72% had hs-cTnT above the LoD (median 5 [Q1-3 2-11] ng/L). There was a graded relationship between hs-cTn concentrations and coronary artery calcium. Only hs-cTnI remained associated with CAD50 in adjusted analyses (OR 1.20 95% Confidence Interval [1.05-1.38]), p = 0.009). The C-statistics for hs-cTnI and hs-cTnT were 0.65 (95% CI [0.60-0.69]) and 0.60 (0.56-0.64). The highest specificity and negative predictive values for CAD50 were in the lowest NORRISK2-tertile. hs-cTn concentrations provide diagnostic information in patients with suspected CCS, with superior performance of hs-cTnI compared to hs-cTnT in regard to CAD50. The diagnostic performance appeared best in those with low cardiovascular risk.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Troponina I/análise , Troponina T/análise , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Angiografia por Tomografia Computadorizada/métodos , Doença da Artéria Coronariana/metabolismo , Vasos Coronários , Feminino , Coração/fisiologia , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Valor Preditivo dos Testes , Troponina I/metabolismo , Troponina T/metabolismo
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