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1.
Am J Physiol Endocrinol Metab ; 319(1): E217-E231, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32516026

RESUMO

We previously demonstrated that circulating extracellular vesicles (EVs) from patients with valvular heart disease (VHD; vEVs) contain inflammatory components and inhibit endothelium-dependent vasodilation. Neutrophil chemotaxis plays a key role in renal dysfunction, and dexmedetomidine (DEX) can reduce renal dysfunction in cardiac surgery. However, the roles of vEVs in neutrophil chemotaxis and effects of DEX on vEVs are unknown. Here, we investigated the impact of vEVs on neutrophil chemotaxis in kidneys and the influence of DEX on vEVs. Circulating EVs were isolated from healthy subjects and patients with VHD. The effects of EVs on chemokine generation, forkhead box protein O3a (FOXO3a) pathway activation and neutrophil chemotaxis on cultured human umbilical vein endothelial cells (HUVECs) and kidneys in mice and the influence of DEX on EVs were detected. vEVs increased FOXO3a expression, decreased phosphorylation of Akt and FOXO3a, promoted FOXO3a nuclear translocation, and activated the FOXO3a signaling pathway in vitro. DEX pretreatment reduced vEV-induced CXCL4 and CCL5 expression and neutrophil chemotaxis in cultured HUVECs via the FOXO3a signaling pathway. vEVs were also found to suppress Akt phosphorylation and activate FOXO3a signaling to increase plasma levels of CXCL4 and CCL5 and neutrophil accumulation in kidney. The overall mechanism was inhibited in vivo with DEX pretreatment. Our data demonstrated that vEVs induced CXCL4-CCL5 to stimulate neutrophil infiltration in kidney, which can be inhibited by DEX via the FOXO3a signaling. Our findings reveal a unique mechanism involving vEVs in inducing neutrophils chemotaxis and may provide a novel basis for using DEX in reducing renal dysfunction in valvular heart surgery.


Assuntos
Quimiotaxia de Leucócito/imunologia , Vesículas Extracelulares/imunologia , Doenças das Valvas Cardíacas/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Rim/imunologia , Neutrófilos/imunologia , Insuficiência Renal/imunologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Adulto , Animais , Estudos de Casos e Controles , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CCL5/imunologia , Quimiocina CCL5/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Dexmedetomidina/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Feminino , Proteína Forkhead Box O3/efeitos dos fármacos , Proteína Forkhead Box O3/imunologia , Proteína Forkhead Box O3/metabolismo , Doenças das Valvas Cardíacas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Fosforilação , Fator Plaquetário 4/efeitos dos fármacos , Fator Plaquetário 4/imunologia , Fator Plaquetário 4/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Insuficiência Renal/metabolismo , Vasodilatação
2.
J Cardiovasc Pharmacol ; 72(4): 176-185, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29985281

RESUMO

Simvastatin treatment is cardioprotective in patients undergoing noncoronary artery cardiac surgery. However, the mechanisms by which simvastatin treatment protects the myocardium under these conditions are not fully understood. Seventy patients undergoing noncoronary cardiac surgery, 35 from a simvastatin treatment group and 35 from a control treatment group, were enrolled in our clinical study. Simvastatin (20 mg/d) was administered preoperatively for 5-7 days. Myocardial tissue biopsies were taken before and after surgery. Apoptosis was detected by TUNEL staining. The expressions of Bcl-2 and Bak in myocardial tissue were detected by immunoblotting. The expressions of miRNA and Bcl-2 mRNA were detected by quantitative real-time polymerase chain reaction assays. Cardiomyocytes were isolated from rat and cultured cells. MiR-15a-5p mimic was transfected into cardiomyocytes, and the Bcl-2 was detected by immunoblotting. TUNEL staining showed significantly less myocardial apoptosis in the simvastatin treatment group when compared with the control treatment group. Protein expression of Bcl-2 was increased in the simvastatin treatment group before surgery, and Bak expression was increased in the control treatment group after surgery. Further comparisons showed that Bcl-2/Bak ratios were reduced in the control treatment group but were not significantly changed in the simvastatin treatment group after surgery. Furthermore, microarray assays revealed that miR-15a-5p was significantly decreased by simvastatin treatment. This was validated by quantitative real-time polymerase chain reaction analysis. MiR-15a-5p was predicted to target Bcl-2 mRNA at nucleotide positions 2529-2536. This was validated by luciferase binding assays. Coincident with the change in miR-15a-5p, the mRNA expression of Bcl-2 was increased in the simvastatin treatment group. MiR-15a-5p mimic significantly inhibited Bcl-2 expression in cardiomyocytes. Our findings strongly suggest that simvastatin treatment preoperatively protected the myocardium in patients undergoing noncoronary artery cardiac surgery, at least in part, by inhibiting apoptosis via suppressing miR-15a-5p expression, leading to increasing expression of Bcl-2 and decreasing expression of Bak.


Assuntos
Apoptose/efeitos dos fármacos , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Cardiopatias/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , MicroRNAs/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Sinvastatina/administração & dosagem , Adulto , Animais , Células Cultivadas , China , Esquema de Medicação , Feminino , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/efeitos adversos , Resultado do Tratamento , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo
3.
Sci China Life Sci ; 67(3): 475-487, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37219765

RESUMO

Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury (ALI), including acute respiratory distress syndrome (ARDS), in patients after cardiac surgery. We previously found that post-operative patients showed an increase in endothelial cell-derived extracellular vesicles (eEVs) with components of coagulation and acute inflammatory responses. However, the mechanism underlying the onset of ALI owing to the release of eEVs after cardiopulmonary bypass, remains unclear. Plasma plasminogen-activated inhibitor-1 (PAI-1) and eEV levels were measured in patients with cardiopulmonary bypass. Endothelial cells and mice (C57BL/6, Toll-like receptor 4 knockout (TLR4-/-) and inducible nitric oxide synthase knockout (iNOS-/-)) were challenged with eEVs isolated from PAI-1-stimulated endothelial cells. Plasma PAI-1 and eEVs were remarkably enhanced after cardiopulmonary bypass. Plasma PAI-1 elevation was positively correlated with the increase in eEVs. The increase in plasma PAI-1 and eEV levels was associated with post-operative ARDS. The eEVs derived from PAI-1-stimulated endothelial cells could recognize TLR4 to stimulate a downstream signaling cascade identified as the Janus kinase 2/3 (JAK2/3)-signal transducer and activator of transcription 3 (STAT3)-interferon regulatory factor 1 (IRF-1) pathway, along with iNOS induction, and cytokine/chemokine production in vascular endothelial cells and C57BL/6 mice, ultimately contributing to ALI. ALI could be attenuated by JAK2/3 or STAT3 inhibitors (AG490 or S3I-201, respectively), and was relieved in TLR4-/- and iNOS-/- mice. eEVs activate the TLR4/JAK3/STAT3/IRF-1 signaling pathway to induce ALI/ARDS by delivering follistatin-like protein 1 (FSTL1), and FSTL1 knockdown in eEVs alleviates eEV-induced ALI/ARDS. Our data thus demonstrate that cardiopulmonary bypass may increase plasma PAI-1 levels to induce FSTL1-enriched eEVs, which target the TLR4-mediated JAK2/3/STAT3/IRF-1 signaling cascade and form a positive feedback loop, leading to ALI/ARDS after cardiac surgery. Our findings provide new insight into the molecular mechanisms and therapeutic targets for ALI/ARDS after cardiac surgery.


Assuntos
Lesão Pulmonar Aguda , Vesículas Extracelulares , Proteínas Relacionadas à Folistatina , Síndrome do Desconforto Respiratório , Animais , Humanos , Camundongos , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Proteínas Relacionadas à Folistatina/metabolismo , Proteínas Relacionadas à Folistatina/uso terapêutico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Inibidor 1 de Ativador de Plasminogênio/uso terapêutico , Síndrome do Desconforto Respiratório/etiologia , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/uso terapêutico
4.
Front Cardiovasc Med ; 9: 893609, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35571221

RESUMO

Background: Acute lung injury (ALI) is a common complication after cardiac surgery with cardiopulmonary bypass (CPB). No precise way, however, is currently available to predict its occurrence. We and others have demonstrated that microparticles (MPs) can induce ALI and were increased in patients with ALI. However, whether MPs can be used to predict ALI after cardiac surgery with CPB remains unknown. Methods: In this prospective study, 103 patients undergoing cardiac surgery with CPB and 53 healthy subjects were enrolled. MPs were isolated from the plasma before, 12 h after, and 3 d after surgery. The size distributions of MPs were measured by the LitesizerTM 500 Particle Analyzer. The patients were divided into two subgroups (ALI and non-ALI) according to the diagnosis of ALI. Descriptive and correlational analyzes were conducted between the size distribution of MPs and clinical data. Results: Compared to the non-ALI group, the size at peak and interquartile range (IQR) of MPs in patients with ALI were smaller, but the peak intensity of MPs is higher. Multivariate logistic regression analysis indicated that the size at peak of MPs at postoperative 12 h was an independent risk factor for ALI. The area under the curve (AUC) of peak diameter at postoperative 12 h was 0.803. The best cutoff value of peak diameter to diagnose ALI was 223.05 nm with a sensitivity of 88.0% and a negative predictive value of 94.5%. The AUC of IQR at postoperative 12 h was 0.717. The best cutoff value of IQR to diagnose ALI was 132.65 nm with a sensitivity of 88.0% and a negative predictive value of 92.5%. Combining these two parameters, the sensitivity reached 92% and the negative predictive value was 96%. Conclusions: Our findings suggested that the size distribution of MPs could be a novel biomarker to predict and exclude ALI after cardiac surgery with CPB.

5.
J Cardiovasc Transl Res ; 15(6): 1414-1423, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35879589

RESUMO

The aim of this study was to investigate whether pentraxin 3 (PTX3) in microvesicles (MVs) can be a valuable biomarker for the prediction of acute heart failure (AHF) after cardiac surgery with cardiopulmonary bypass (CPB). One hundred and twenty-four patients undergoing cardiac surgery with CPB were included and analyzed (29 with AHF and 95 without AHF). The concentrations of PTX3 in MVs isolated from plasma were measured by ELISA kits before, 12 h, and 3 days after surgery. Patients' demographics, medical history, surgical data, and laboratory results were collected. The levels of PTX3 in MVs were significantly elevated during perioperative surgery, which was increased more in the AHF group. The concentrations of PTX3 in MVs at postoperative 12 h were independent risk factors for AHF with the area under the ROC curve of 0.920. The concentration of PTX3 in MVs may be a novel biomarker for prediction of AHF after cardiac surgery.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Insuficiência Cardíaca , Humanos , Ponte Cardiopulmonar/efeitos adversos , Componente Amiloide P Sérico/análise , Proteína C-Reativa , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Biomarcadores , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/cirurgia
6.
Atherosclerosis ; 328: 83-91, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34118596

RESUMO

BACKGROUND AND AIMS: The apolipoprotein A-I mimetic peptide D-4F, among its anti-atherosclerotic effects, improves vasodilation through mechanisms not fully elucidated yet. METHODS: Low-density lipoprotein (LDL) receptor null (LDLr-/-) mice were fed Western diet with or without D-4F. We then measured atherosclerotic lesion formation, endothelial nitric oxide synthase (eNOS) phosphorylation and its association with heat shock protein 90 (HSP90), nitric oxide (NO) and superoxide anion (O2•-) production, and tetrahydrobiopterin (BH4) and GTP-cyclohydrolase 1 (GCH-1) concentration in the aorta. Human umbilical vein endothelial cells (HUVECs) and aortas were treated with oxidized LDL (oxLDL) with or without D-4F; subsequently, BH4 and GCH-1 concentration, NO and O2•- production, eNOS association with HSP90, and endothelium-dependent vasodilation were measured. RESULTS: Unexpectedly, eNOS phosphorylation, eNOS-HSP90 association, and O2•- production were increased, whereas BH4 and GCH-1 concentration and NO production were reduced in atherosclerosis. D-4F significantly inhibited atherosclerosis, eNOS phosphorylation, eNOS-HSP90 association, and O2•- generation but increased NO production and BH4 and GCH-1 concentration. OxLDL reduced NO production and BH4 and GCH-1 concentration but enhanced O2•- generation and eNOS association with HSP90, and impaired endothelium-dependent vasodilation. D-4F inhibited the overall effects of oxLDL. CONCLUSIONS: Hypercholesterolemia enhanced uncoupled eNOS activity by decreasing GCH-1 concentration, thereby reducing BH4 levels. D-4F reduced uncoupled eNOS activity by increasing BH4 levels through GCH-1 expression and decreasing eNOS phosphorylation and eNOS-HSP90 association. Our findings elucidate a novel mechanism by which hypercholesterolemia induces atherosclerosis and D-4F inhibits it, providing a potential therapeutic approach.


Assuntos
Aterosclerose , Óxido Nítrico Sintase Tipo III , Animais , Apolipoproteína A-I , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Biopterinas/análogos & derivados , Células Endoteliais , Endotélio Vascular , GTP Cicloidrolase , Guanosina Trifosfato , Camundongos , Óxido Nítrico , Peptídeos , Superóxidos
7.
Ann Transl Med ; 9(9): 786, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34268399

RESUMO

BACKGROUND: Current diagnostic strategies for acute kidney injury (AKI) after cardiac surgery with cardiopulmonary bypass (CPB) are nonspecific and limited. Previously, we demonstrated that circulating microparticles (MPs) in patients with valve heart disease (VHD) and congenital heart diseases (CHD) induce endothelial dysfunction and neutrophil chemotaxis, which may result in kidney injury. We also found that circulating MPs increase after cardiac surgery with CPB and are related to cardiac function. However, the relationship between circulating MPs and AKI after CPB is unknown. METHODS: Eighty-five patients undergoing cardiac surgery with CPB were enrolled. Patients were divided into AKI and non-AKI groups based on the serum creatinine levels at 12 h and 3 d post-CPB. Circulating MPs were isolated from plasma, and their levels including its subtypes were detected by flow cytometer. Independent risk factors for the CPB-associated AKI (CPB-AKI) were determined by multivariate logistic regression analysis. Receiver operating characteristic (ROC) analysis was used to measure the prognostic potential of CPB-AKI. RESULTS: The morbidity of AKI at 12 h and 3 d after cardiac surgery with CPB was 40% and 31.76%, respectively. The concentrations of total MPs and platelet-derived MPs (PMP) remained unchanged at 12 h and then increased at 3 d post-CPB, while that of endothelial-derived MPs (EMP) increased at both time points. In patients with AKI, PMP and EMP were elevated compared with the patients without AKI. However, no significant change was detected on monocyte-derived MPs (MMP) at 12 h and 3 d post-CPB. The logistic regression analysis showed that EMP was the independent risk factor for AKI both at 12 h and 3 d post-CPB. The area under ROC for the concentrations of EMP at 12 h and 3 d post-CPB was 0.86 and 0.91, with the specificity up to 0.88 and 0.91, respectively. CONCLUSIONS: Circulating EMP may serve as a potential biomarker of AKI after cardiac surgery with CPB.

8.
Shock ; 52(5): 487-496, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30601407

RESUMO

We recently demonstrated that circulating microparticles (MPs) from patients with valvular heart diseases (VHD) subjected to cardiac surgery impaired endothelial function and vasodilation. However, it is unknown whether or not the protein composition of these circulating MPs actually changes in response to the disease and the surgery. Circulating MPs were isolated from age-matched control subjects (n = 50) and patients (n = 50) with VHD before and 72 h after cardiac surgery. Proteomics study was performed by liquid chromatography and mass spectrometry combined with isobaric tags for relative and absolute quantification technique. The differential proteins were identified by ProteinPilot, some of which were validated by Western blotting. Bio-informatic analysis of differential proteins was carried out. A total of 849 proteins were identified and 453 proteins were found in all three groups. Meanwhile, 165, 39, and 80 proteins were unique in the control, pre-operation, and postoperation groups respectively. The unique proteins were different in localization, molecular function, and biological process. The pro-inflammatory proteins were increased in VHD patients and more so postoperatively. Proteins related to coagulation were dramatically changed before and after surgery. The protein composition of circulating MPs was changed in patients with VHD undergoing cardiac surgery, which may lead to activation of the systemic inflammatory response and disorders of coagulation.


Assuntos
Coagulação Sanguínea , Micropartículas Derivadas de Células/metabolismo , Doenças das Valvas Cardíacas/sangue , Síndrome de Resposta Inflamatória Sistêmica/sangue , Adulto , Procedimentos Cirúrgicos Cardíacos , Feminino , Doenças das Valvas Cardíacas/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Síndrome de Resposta Inflamatória Sistêmica/cirurgia
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