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1.
PLoS One ; 15(3): e0230358, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208424

RESUMO

Endothelial dysfunction is a critical event in vascular inflammation characterized, in part, by elevated surface expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is heavily N-glycosylated, and like other surface proteins, it is largely presumed that fully processed, complex N-glycoforms are dominant. However, our recent studies suggest that hypoglycosylated or high mannose (HM)-ICAM-1 N-glycoforms are also expressed on the cell surface during endothelial dysfunction, and have higher affinity for monocyte adhesion and regulate outside-in endothelial signaling by different mechanisms. Whether different ICAM-1 N-glycoforms are expressed in vivo during disease is unknown. In this study, using the proximity ligation assay, we assessed the relative formation of high mannose, hybrid and complex α-2,6-sialyated N-glycoforms of ICAM-1 in human and mouse models of atherosclerosis, as well as in arteriovenous fistulas (AVF) of patients on hemodialysis. Our data demonstrates that ICAM-1 harboring HM or hybrid epitopes as well as ICAM-1 bearing α-2,6-sialylated epitopes are present in human and mouse atherosclerotic lesions. Further, HM-ICAM-1 positively associated with increased macrophage burden in lesions as assessed by CD68 staining, whereas α-2,6-sialylated ICAM-1 did not. Finally, both HM and α-2,6-sialylated ICAM-1 N-glycoforms were present in hemodialysis patients who had AVF maturation failure compared to successful AVF maturation. Collectively, these data provide evidence that HM- ICAM-1 N-glycoforms are present in vivo, and at levels similar to complex α-2,6-sialylated ICAM-1 underscoring the need to better understand their roles in modulating vascular inflammation.


Assuntos
Aterosclerose/patologia , Endotélio Vascular/patologia , Inflamação/patologia , Molécula 1 de Adesão Intercelular/imunologia , Isoformas de Proteínas/análise , Adulto , Idoso , Animais , Artérias/citologia , Artérias/patologia , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Aterosclerose/imunologia , Modelos Animais de Doenças , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Epitopos/análise , Epitopos/imunologia , Epitopos/metabolismo , Feminino , Glicosilação , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/imunologia , Molécula 1 de Adesão Intercelular/análise , Molécula 1 de Adesão Intercelular/metabolismo , Macrófagos/imunologia , Masculino , Manose/metabolismo , Camundongos , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Ácido N-Acetilneuramínico/metabolismo , Isoformas de Proteínas/metabolismo , Adulto Jovem
2.
Phytomedicine ; 67: 153158, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31999981

RESUMO

Background Shengui Sansheng Pulvis (SSP) has about 300 years history used for stroke treatment, and evidences suggest it has beneficial effects on neuro-angiogenesis and cerebral energy metabolic amelioration post-stroke. However, its protective action and mechanisms on blood-brain barrier (BBB) is still unknown. Purpose Based on multiple neuroprotective properties of vasoactive intestinal peptide (VIP) in neurological disorders, we investigate if SSP maintaining BBB integrity is associated with VIP pathway in rat permanent middle cerebral artery occlusion (MCAo) model. Methods Three doses of SSP extraction were administered orally. Evaluations of motor and balance abilities and detection of brain edema were performed, and BBB permeability were assessed by Evans blue (EB) staining. Primary brain microvascular endothelial cells (BMECs) were subjected to oxygen-glucose deprivation, and incubated with high dose SSP drug-containing serum and VIP-antagonist respectively. Transendothelial electrical resistance (TEER) assay and Tetramethylrhodamine isothiocyanate (TRITC)-dextran (4.4 kDa) and fluorescein isothiocyanate (FITC)-dextran (70 kDa) were used to evaluate the features of paracellular junction. Western blot detected the expressions of Claudin-5, ZO-1, Occludin and VE-cadherin, matrix metalloproteinase (MMP) 2/9 and VIP receptors 1/2, and immunofluorescence staining tested VIP and Claudin-5 expressions. Results Our results show that SSP significantly reduces EB infiltration in dose-dependent manner in vivo and attenuates TRITC- dextran and FITC-dextran diffusion in vitro, and strengthens endothelial junctional complexes as represented by decreasing Claudin-5, ZO-1, Occludin and VE-cadherin degradations and MMP 2/9 expression, as well as promoting TEER in BMECs after ischemia. Moreover, it suggests that SSP notably enhances VIP and its receptors 1/2 expressions. VIP-antagonist exacerbates paracellular barrier of BMECs, while the result is reversed after incubation with high dose SSP drug-containing serum. Additionally, SSP also improve brain edema and motor and balance abilities after ischemic stroke. Conclusions we firstly demonstrate that the ameliorated efficacy of SSP on BBB permeability is related to the enhancements of VIP and its receptors, suggesting SSP might be an effective therapeutic agent on maintaining BBB integrity post-stroke.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Claudina-5/metabolismo , Medicamentos de Ervas Chinesas/química , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Permeabilidade , Ratos Endogâmicos , Receptores Tipo II de Peptídeo Intestinal Vasoativo/metabolismo , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/metabolismo , Acidente Vascular Cerebral/fisiopatologia
3.
PLoS Genet ; 16(1): e1008538, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917787

RESUMO

Genome-wide association studies have identified multiple novel genomic loci associated with vascular diseases. Many of these loci are common non-coding variants that affect the expression of disease-relevant genes within coronary vascular cells. To identify such genes on a genome-wide level, we performed deep transcriptomic analysis of genotyped primary human coronary artery smooth muscle cells (HCASMCs) and coronary endothelial cells (HCAECs) from the same subjects, including splicing Quantitative Trait Loci (sQTL), allele-specific expression (ASE), and colocalization analyses. We identified sQTLs for TARS2, YAP1, CFDP1, and STAT6 in HCASMCs and HCAECs, and 233 ASE genes, a subset of which are also GTEx eGenes in arterial tissues. Colocalization of GWAS association signals for coronary artery disease (CAD), migraine, stroke and abdominal aortic aneurysm with GTEx eGenes in aorta, coronary artery and tibial artery discovered novel candidate risk genes for these diseases. At the CAD and stroke locus tagged by rs2107595 we demonstrate colocalization with expression of the proximal gene TWIST1. We show that disrupting the rs2107595 locus alters TWIST1 expression and that the risk allele has increased binding of the NOTCH signaling protein RBPJ. Finally, we provide data that TWIST1 expression influences vascular SMC phenotypes, including proliferation and calcification, as a potential mechanism supporting a role for TWIST1 in CAD.


Assuntos
Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas Nucleares/genética , Proteína 1 Relacionada a Twist/genética , Doenças Vasculares/genética , Células Cultivadas , Vasos Coronários/citologia , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Transcriptoma , Proteína 1 Relacionada a Twist/metabolismo
4.
World Neurosurg ; 136: e469-e475, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31953100

RESUMO

OBJECTIVE: The present study aimed to characterize the mechanism of fluid shear stress (FSS)-induced endothelial cell (EC) injury via protein kinase C alpha (PKCα)-mediated vascular endothelial cadherin (VE-cadherin) and p120-catenin (p120ctn) expression. METHODS: We designed a T chamber system that produced stable FSS on ECs in vitro. Human umbilical vein endothelial cells (HUVECs) in which PKCα was knocked down and normal HUVECs were cultured on the coverslips. FSS was impinged on these 2 types of ECs for 0 hours and 6 hours. The morphology and density of HUVECs were evaluated, and expression levels of phosphorylated PKCα, p120-catenin (p120ctn), VE-cadherin, phosphorylated p120ctn at S879 (p-S879p120ctn), and nuclear factor kappa B (NF-κB) were analyzed by Western blot. RESULTS: HUVECs exposed to FSS were characterized by a polygonal shape and decreased cell density. The phosphorylated PKCα level was increased under FSS at 6 hours (P < 0.05). In normal HUVECs during FSS, p120ctn and VE-cadherin were decreased, whereas p-S879p120ctn and NF-κB were increased, at 6 hours (P < 0.05). In HUVECs after PKCα knockdown, p120ctn and VE-cadherin were not significantly changed (P > 0.05), p-S879p120ctn was undetectable, but NF-κB was decreased (P < 0.05) at 6 hours. CONCLUSIONS: The possible mechanism of FSS-induced EC injury may be as follows: 1) PKCα induces low expression of p120ctn, which leads to activation of NF-κB and degradation of VE-cadherin; 2) PKCα-mediated phosphorylation of p120ctn at S879 disrupts p120ctn binding to VE-cadherin.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Cateninas/metabolismo , Células Endoteliais da Veia Umbilical Humana/fisiologia , Proteína Quinase C-alfa/metabolismo , Estresse Fisiológico/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Técnicas de Silenciamento de Genes , Humanos
5.
Braz J Med Biol Res ; 53(2): e8616, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994599

RESUMO

Previous research has shown that suppression of miR-383 can prevent inflammation of the endothelium, as well as postpone the development of atherosclerosis. However, the role of miR-383 in endothelial cell apoptosis in diabetes remains unclear. The aim of this study was to investigate the function of miR-383 in high glucose-induced apoptosis and oxidative stress in endothelial cells. A series of experiments involving qualitative polymerase chain reaction, cell transfection, luciferase assay, assessment of cell death, detection of catalase and superoxide dismutase concentrations, detection of intracellular reactive oxygen species (ROS), and western blot analysis were performed in this study. We found that miR-383 expression was promoted, while NAD+-dependent deacetylase and sirtuin 1 (SIRT1) expressions were suppressed in the endothelium of the aorta in db/db mice as well as in human umbilical vein endothelial cells, which were treated with high glucose (HG). Increased expression of miR-383 decreased expression of SIRT1, while suppression of miR-383 promoted expression of SIRT1 in human umbilical vein endothelial cells (HUVECs). Furthermore, suppression of miR-383 following transfection with miR-383 suppressor repressed cell death and generation of ROS in HUVECs. SIRT1 knockdown by siRNA-SIRT1 reversed the suppressive effect of miR-383 inhibition on ROS production and cell apoptosis induced by HG treatment. Overall, the findings of our research suggested that suppression of miR-383 repressed oxidative stress and reinforced the activity of endothelial cells by upregulation of SIRT1 in db/db mice, and targeting miR-383 might be promising for effective treatment of diabetes.


Assuntos
Apoptose/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Glucose/farmacologia , MicroRNAs/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
6.
Proc Natl Acad Sci U S A ; 117(6): 3157-3166, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31988136

RESUMO

Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth, and metastasis are not well understood. In this paper, we show that S1PR1 is expressed and active in tumor vessels. Murine tumor vessels that lack S1PR1 in the vascular endothelium (S1pr1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1pr1, 2, and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1pr1 ECTG) show less branching, tortuosity, and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1pr1 ECKO, whereas S1pr1 ECTG showed smaller tumors and reduced metastasis. Furthermore, antitumor activity of a chemotherapeutic agent (doxorubicin) and immune checkpoint inhibitor blocker (anti-PD-1 antibody) were more effective in S1pr1 ECTG than in the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth and metastasis, thus enhancing antitumor therapies in mouse models. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy of solid tumors.


Assuntos
Antineoplásicos/farmacologia , Neovascularização Patológica/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Animais , Permeabilidade Capilar/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Camundongos , Camundongos Knockout , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Receptores de Esfingosina-1-Fosfato/genética
7.
J Surg Res ; 246: 568-583, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31653415

RESUMO

BACKGROUND: Coagulation disturbances in several liver diseases lead to thrombin generation, which triggers intracellular injury via activation of protease-activated receptor-1 (PAR-1). Little is known about the thrombin/PAR-1 pathway in hepatic ischemia-reperfusion injury (IRI). The present study aimed to clarify whether a newly selective PAR-1 antagonist, vorapaxar, can attenuate liver damage caused by hepatic IRI, with a focus on apoptosis and the survival-signaling pathway. METHODS: A 60-min hepatic partial-warm IRI model was used to evaluate PAR-1 expression in vivo. Subsequently, IRI mice were treated with or without vorapaxar (with vehicle). In addition, hepatic sinusoidal endothelial cells (SECs) pretreated with or without vorapaxar (with vehicle) were incubated during hypoxia-reoxygenation in vitro. RESULTS: In naïve livers, PAR-1 was confirmed by immunohistochemistry and immunofluorescence analysis to be located on hepatic SECs, and IRI strongly enhanced PAR-1 expression. In IRI mice models, vorapaxar treatment significantly decreased serum transaminase levels, improved liver histological damage, reduced the number of apoptotic cells as evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining (median: 135 versus 25, P = 0.004), and induced extracellular signal-regulated kinase 1/2 (ERK 1/2) cell survival signaling (phospho-ERK/total ERK 1/2: 0.96 versus 5.34, P = 0.004). Pretreatment of SECs with vorapaxar significantly attenuated apoptosis and induced phosphorylation of ERK 1/2 in vitro (phospho-ERK/total ERK 1/2: 0.66 versus 3.04, P = 0.009). These changes were abolished by the addition of PD98059, the ERK 1/2 pathway inhibitor, before treatment with vorapaxar. CONCLUSIONS: The results of the present study revealed that hepatic IRI induces significant enhancement of PAR-1 expression on SECs, which may be associated with suppression of survival signaling pathways such as ERK 1/2, resulting in severe apoptosis-induced hepatic damage. Thus, the selective PAR-1 antagonist attenuates hepatic IRI through an antiapoptotic effect by the activation of survival-signaling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Lactonas/administração & dosagem , Fígado/irrigação sanguínea , Piridinas/administração & dosagem , Receptor PAR-1/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Animais , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Receptor PAR-1/metabolismo , Traumatismo por Reperfusão/etiologia , Trombina/metabolismo
8.
J Surg Res ; 246: 274-283, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31614325

RESUMO

BACKGROUND: Fluid therapy influences glycocalyx shedding; however, the effect of this intervention on glycocalyx shedding in patients with glioma remains unclear. In this study, we have investigated glycocalyx shedding and cerebral metabolism during colloid loading in patients with and without glioma. METHODS: Forty patients undergoing general anesthesia were assigned to the glioma brain group (n = 20) or the normal brain group (n = 20); patients in the normal brain group were undergoing partial hepatectomy to treat liver cancer. All patients were subjected to 15 mL/kg hydroxyethyl starch (HES) loading after the induction of anesthesia. Glycocalyx shedding, reflected by syndecan-1 and heparan sulfate levels at the jugular venous bulb, was measured in both groups. We also evaluated cerebral metabolism parameters, including jugular venous oxygen saturation (SjvO2), arterial-jugular venous differences in oxygen (CajvO2), glucose (A-JvGD), lactate (A-JvLD), the cerebral extraction ratio for oxygen (CERO2), and the oxygen-glucose index. RESULTS: Our results showed that patients in the glioma brain group had lower preoperative basal syndecan-1 shedding in plasma than patients in the normal brain group. The hematocrit (Hct)-corrected syndecan-1 level was significantly increased after 15 mL/kg HES fluid administration (19.78 ± 3.83 ng/mL) compared with the Hct-correct baseline syndecan-1 level (15.67 ± 2.35 ng/mL) in patients in the glioma brain group. Similarly, for patients in the normal brain group, Hct-corrected syndecan-1 level was significantly increased after HES loading (34.71 ± 12.83 ng/mL) compared with the baseline syndecan-1 level (26.07 ± 12.52 ng/mL). However, there were no intergroup or intragroup differences in Hct-corrected heparan sulfate levels at any time point. Our study also showed that the SjvO2 was lower and CajvO2 and CERO2 were higher in the glioma brain group at 30 min after HES loading. Intragroup analysis showed that CERO2 and CajvO2 increased after general anesthesia compared with the baseline values in the glioma brain group. In contrast, cerebral metabolism in the normal brain group was unchanged during perioperative period. There were no significant differences in oxygen-glucose index between the two groups throughout the study period. CONCLUSIONS: Preoperative 15 mL/kg HES loading had similar effects on systemic glycocalyx shedding in both the glioma brain and normal brain groups, although patients in the normal brain group had higher levels of plasma syndecan-1. Furthermore, the intraoperative anesthetic management may substantially influence cerebral metabolism in patients with glioma.


Assuntos
Encéfalo/metabolismo , Hidratação/efeitos adversos , Glicocálix/efeitos dos fármacos , Derivados de Hidroxietil Amido/efeitos adversos , Cuidados Pré-Operatórios/efeitos adversos , Adulto , Encéfalo/efeitos dos fármacos , Encéfalo/cirurgia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirurgia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Hidratação/métodos , Glioma/metabolismo , Glioma/cirurgia , Glicocálix/metabolismo , Heparitina Sulfato/análise , Heparitina Sulfato/metabolismo , Humanos , Derivados de Hidroxietil Amido/administração & dosagem , Cuidados Intraoperatórios/efeitos adversos , Cuidados Intraoperatórios/métodos , Veias Jugulares/química , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/métodos , Estudos Prospectivos , Sindecana-1/sangue , Sindecana-1/metabolismo
9.
Toxicol In Vitro ; 62: 104694, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31655124

RESUMO

AIM: Hyperglycemia status induces endothelial dysfunction, although the underlying pathogenic mechanisms are not fully understood. There are several studies connecting sugar/sweetened beverages to the cardiovascular disease. Currently, many sweeteners have been extensively introduced into lifestyle to normalize blood glucose levels without altering the sweet taste. However, there is growing concern for their impact on metabolic health. METHODS: Human endothelial cells were treated with Glucose, Fructose, Aspartame, Rebaudioside A, Stevioside, or Steviol. Morphological characteristics, in vitro angiogenesis and array gene expression were analyzed. RESULTS: High-glucose and fructose concentrations significantly decreased cell features such as angiogenic capability. Interestingly, non-caloric sweeteners did not significantly modified all cell characteristics and they did not compromised cell angiogenic ability. Array gene expression analysis revealed that the chemokine fractalkine (CX3CL1) and the enzyme transferase (HPRT1) were always significantly upregulated and downregulated respectively, after glucose and fructose treatments (P > .05), whereas they were non-differentially expressed with all the other sweeteners. Interestingly, both genes are considered as cardiovascular disease risk biomarkers. Specifically, upregulation of CX3CL1/CX3CR1 occurs in the human placenta and serum levels of the ligand are associated with markers of insulin resistance in GDM. CONCLUSIONS: Differently from glucose and fructose, steviol glycosides do not damage endothelial cells. Prospective preclinical studies and clinical trials are warranted to confirm the long-term safety of such compounds.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Edulcorantes/farmacologia , Aspartame/farmacologia , Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Diterpenos de Caurano/farmacologia , Endotélio Vascular/citologia , Feminino , Frutose/farmacologia , Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Glucosídeos/farmacologia , Humanos , Hipoxantina Fosforribosiltransferase/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Estudos Prospectivos
10.
Ren Fail ; 42(1): 19-29, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31858861

RESUMO

Renal microvascular lesions, common in lupus nephritis (LN), are associated with long-term poor outcomes. There are mainly five pathological types of renal microvascular lesions in LN: (1) vascular immune complex deposits (ICD), (2) arteriosclerosis (AS), (3) thrombotic microangiopathy (TMA), (4) non-inflammatory necrotizing vasculopathy (NNV), and (5) true renal vasculitis (TRV). The pathogenesis of renal microvascular lesions in LN remains to be elucidated. The activation and dysfunction of endothelial cells, in addition to the contribution of immune system dysfunction, especially the immune complex-induced vascular inflammation and antiphospholipid antibody-associated thrombotic events, are key mechanisms in the development of vascular lesions in LN that need to be further investigated. Alteration of the microvascular environment produces an acute immunological response that recruits immune cells, such as T cells, monocytes, and macrophages, which induces platelet aggregation with microthrombus formation. There is also increased cytotoxicity caused by cytokines produced by immune cells in the kidney. Identifying the mechanism underlying the pathogenesis of renal microvascular lesions in LN might provide potential targets for the development of novel therapies.


Assuntos
Rim/irrigação sanguínea , Nefrite Lúpica/complicações , Doenças Vasculares/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Rim/imunologia , Nefrite Lúpica/imunologia , Microvasos/imunologia , Microvasos/patologia , Literatura de Revisão como Assunto , Doenças Vasculares/patologia
11.
J Surg Res ; 245: 273-280, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31421373

RESUMO

BACKGROUND: Transplantation of lungs procured after donation after circulatory death (DCD) is challenging because postmortem metabolic degradation may engender susceptibility to ischemia-reperfusion (IR) injury. Because oxidative mitochondrial DNA (mtDNA) damage has been linked to endothelial barrier disruption in other models of IR injury, here we used a fusion protein construct targeting the DNA repair 8-oxoguanine DNA glycosylase-1 (OGG1) to mitochondria (mtOGG1) to determine if enhanced repair of mtDNA damage attenuates endothelial barrier dysfunction after IR injury in a rat model of lung procurement after DCD. MATERIALS AND METHODS: Lungs excised from donor rats 1 h after cardiac death were cold stored for 2 h after which they were perfused ex vivo in the absence and presence of mt-OGG1 or an inactive mt-OGG1 mutant. Lung endothelial barrier function and mtDNA integrity were determined during and at the end of perfusion, respectively. RESULTS AND CONCLUSIONS: Mitochondria-targeted OGG1 attenuated indices of lung endothelial dysfunction incurred after a 1h post-mortem period. Oxidative lung tissue mtDNA damage as well as accumulation of proinflammatory mtDNA fragments in lung perfusate, but not nuclear DNA fragments, also were reduced by mitochondria-targeted OGG1. A repair-deficient mt-OGG1 mutant failed to protect lungs from the adverse effects of DCD procurement. CONCLUSIONS: These findings suggest that endothelial barrier dysfunction in lungs procured after DCD is driven by mtDNA damage and point to strategies to enhance mtDNA repair in concert with EVLP as a means of alleviating DCD-related lung IR injury.


Assuntos
DNA Glicosilases/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas Recombinantes de Fusão/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Aloenxertos/irrigação sanguínea , Aloenxertos/citologia , Aloenxertos/efeitos dos fármacos , Animais , DNA Glicosilases/genética , Reparo do DNA/efeitos dos fármacos , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/genética , Modelos Animais de Doenças , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/citologia , Pulmão/efeitos dos fármacos , Transplante de Pulmão , Masculino , Mitocôndrias/genética , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Perfusão/métodos , Ratos , Proteínas Recombinantes de Fusão/genética , Traumatismo por Reperfusão/patologia , Coleta de Tecidos e Órgãos/métodos
12.
Proc Natl Acad Sci U S A ; 117(1): 717-726, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871197

RESUMO

Mechanosensitive ion channels are crucial for normal cell function and facilitate physiological function, such as blood pressure regulation. So far little is known about the molecular mechanisms of how channels sense mechanical force. Canonical vertebrate epithelial Na+ channel (ENaC) formed by α-, ß-, and γ-subunits is a shear force (SF) sensor and a member of the ENaC/degenerin protein family. ENaC activity in epithelial cells contributes to electrolyte/fluid-homeostasis and blood pressure regulation. Furthermore, ENaC in endothelial cells mediates vascular responsiveness to regulate blood pressure. Here, we provide evidence that ENaC's ability to mediate SF responsiveness relies on the "force-from-filament" principle involving extracellular tethers and the extracellular matrix (ECM). Two glycosylated asparagines, respectively their N-glycans localized in the palm and knuckle domains of αENaC, were identified as potential tethers. Decreased SF-induced ENaC currents were observed following removal of the ECM/glycocalyx, replacement of these glycosylated asparagines, or removal of N-glycans. Endothelial-specific overexpression of αENaC in mice induced hypertension. In contrast, expression of αENaC lacking these glycosylated asparagines blunted this effect. In summary, glycosylated asparagines in the palm and knuckle domains of αENaC are important for SF sensing. In accordance with the force-from-filament principle, they may provide a connection to the ECM that facilitates vascular responsiveness contributing to blood pressure regulation.


Assuntos
Asparagina/metabolismo , Canais Epiteliais de Sódio/metabolismo , Matriz Extracelular/metabolismo , Domínios Proteicos/genética , Animais , Asparagina/química , Modelos Animais de Doenças , Células Endoteliais , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Canais Epiteliais de Sódio/química , Canais Epiteliais de Sódio/genética , Feminino , Glicosilação , Células HEK293 , Humanos , Hipertensão/etiologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Camundongos , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , Oócitos , Técnicas de Patch-Clamp , Mutação Puntual , Polissacarídeos/química , Estresse Mecânico , Xenopus laevis
13.
J Ethnopharmacol ; 247: 112253, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31562952

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal properties of grapes (Vitis vinifera L.) are well known since ancient times. Ethnobotanical grape preparations, like the Ayurvedic Darakchasava are used as cardiotonic and for the treatment of cardiovascular diseases. Dried grape products are also applied in Iranian traditional medicine for memory problems, which are linked to the pathology of brain microvessels, a special part of the cardiovascular system. The anti-inflammatory and protective effects of these traditional preparations on the cardiovascular system are related to their bioactive phenolic compounds. AIM OF THE STUDY: The blood-brain barrier (BBB), formed by brain capillaries, is not only involved in inflammatory and other diseases of the central nervous system, but also in many systemic diseases with an inflammatory component. Dietary obesity is a systemic chronic inflammatory condition in which the peripheral and central vascular system is affected. Among the cerebrovascular changes in obesity defective leptin transport across the BBB related to central leptin resistance is observed. Our aim was to study the protective effects of grape phenolic compounds epicatechin (EC), gallic acid (GA) and resveratrol (RSV) and grape-seed proanthocyanidin-rich extract (GSPE) on a cytokine-induced vascular endothelial inflammation model. Using a culture model of the BBB we investigated cytokine-induced endothelial damage and changes in the expression of leptin receptors and leptin transfer. MATERIALS AND METHODS: For the BBB model, primary cultures of rat brain endothelial cells, glial cells and pericytes were used in co-culture. Cells were treated by tumor necrosis factor-α (TNF-α) and interleukin-1 ß (IL-1ß) (10 ng/ml each) to induce damage. Cell toxicity was evaluated by the measurement of impedance. The expression of leptin receptors was assessed by RT-qPCR and western blot. The production of reactive oxygen species (ROS) and nitric oxide (NO) were detected by fluorescent probes. RESULTS: GSPE (10 µg/ml), EC (10 µM), GA (1 µM) or RSV (10 µM) did not change the viability of brain endothelial cells. The gene expression of the short leptin receptor isoform, Ob-Ra, was up-regulated by GSPE, EC and RSV, while the mRNA levels of Lrp2 and clusterin, clu/ApoJ were not affected. The tested compounds did not change the expression of the long leptin receptor isoform, Ob-Rb. RSV protected against the cytokine-induced increase in albumin permeability of the BBB model. GSPE and EC exerted an antioxidant effect and GSPE increased NO both alone and in the presence of cytokines. The cytokine-induced nuclear translocation of transcription factor NF-κB was blocked by GSPE, GA and RSV. Cytokines increased the mRNA expression of Lrp2 which was inhibited by EC. RSV increased Ob-Ra and Clu in the presence of cytokines. Cytokines elevated leptin transfer across the BBB model, which was not modified by GSPE or RSV. CONCLUSION: Our results obtained on cell culture models confirm that natural grape compounds protect vascular endothelial cells against inflammatory damage in accordance with the ethnopharmacological use of grape preparations in cardiovascular diseases. Furthermore, grape compounds and GSPE, by exerting a beneficial effect on the BBB, may also be considered in the treatment of obesity after validation in clinical trials.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Extrato de Sementes de Uva/farmacologia , Inflamação/tratamento farmacológico , Proantocianidinas/farmacologia , Vitis/química , Animais , Animais Recém-Nascidos , Astrócitos , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/imunologia , Catequina/farmacologia , Células Cultivadas , Citocinas/imunologia , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Etnofarmacologia , Ácido Gálico/farmacologia , Extrato de Sementes de Uva/química , Extrato de Sementes de Uva/uso terapêutico , Humanos , Inflamação/imunologia , Inflamação/patologia , Leptina/imunologia , Leptina/metabolismo , Medicina Ayurvédica/métodos , Cultura Primária de Células , Proantocianidinas/química , Proantocianidinas/uso terapêutico , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptores para Leptina/metabolismo , Resveratrol/farmacologia
14.
Ecotoxicol Environ Saf ; 190: 110077, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31864122

RESUMO

Nε-(carboxymethyl)lysine (CML) is a potentially noxious compound that is causing widespread concern due to its use in various food products. In this study, we investigated CML neurotoxicity via an in vivo experiment with mice, and an in vitro experiment using a 3D microvascular network model (with human brain vascular endothelial cell and human astrocyte) that simulated the blood-brain barrier. We found that CML could induce cell survival status variations, and histopathological changes to the brain. In addition, CML increased levels of oxidative stress, prompted the protein expression of the receptor for advanced glycation end-products (RAGE). CML up-regulated both the gene expression of RAGE, the activating protein-1 (AP-1), the inflammatory cytokines Interleukin-6 (IL-6), vascular cell adhesion molecule1 (VCAM-1), monocyte chemotactic protein1 (MCP-1). We, therefore, postulated that CML has the potential to deleteriously affect the nervous system through oxidative stress and that activation of the p38 MAPK-AP-1 signaling pathway might be implicated in this pathological process.


Assuntos
Lisina/análogos & derivados , Síndromes Neurotóxicas , Animais , Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Técnicas de Cultura de Células , Células Cultivadas , Citocinas/genética , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Manipulação de Alimentos , Humanos , Lisina/toxicidade , Camundongos , Microvasos/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Fator de Transcrição AP-1/metabolismo
15.
Nat Commun ; 10(1): 5705, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836710

RESUMO

Although kidney parenchymal tissue can be generated in vitro, reconstructing the complex vasculature of the kidney remains a daunting task. The molecular pathways that specify and sustain functional, phenotypic and structural heterogeneity of the kidney vasculature are unknown. Here, we employ high-throughput bulk and single-cell RNA sequencing of the non-lymphatic endothelial cells (ECs) of the kidney to identify the molecular pathways that dictate vascular zonation from embryos to adulthood. We show that the kidney manifests vascular-specific signatures expressing defined transcription factors, ion channels, solute transporters, and angiocrine factors choreographing kidney functions. Notably, the ontology of the glomerulus coincides with induction of unique transcription factors, including Tbx3, Gata5, Prdm1, and Pbx1. Deletion of Tbx3 in ECs results in glomerular hypoplasia, microaneurysms and regressed fenestrations leading to fibrosis in subsets of glomeruli. Deciphering the molecular determinants of kidney vascular signatures lays the foundation for rebuilding nephrons and uncovering the pathogenesis of kidney disorders.


Assuntos
Capilares/crescimento & desenvolvimento , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Glomérulos Renais/irrigação sanguínea , Animais , Capilares/citologia , Capilares/metabolismo , Células Cultivadas , Embrião de Mamíferos , Endotélio Vascular/citologia , Endotélio Vascular/crescimento & desenvolvimento , Fator de Transcrição GATA5/genética , Fator de Transcrição GATA5/metabolismo , Perfilação da Expressão Gênica , Humanos , Glomérulos Renais/crescimento & desenvolvimento , Glomérulos Renais/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/metabolismo , Cultura Primária de Células , RNA-Seq , Análise de Célula Única , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
16.
Nat Commun ; 10(1): 5784, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857598

RESUMO

G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, but also serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. However, the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here we show that mechanosensitive histamine H1 receptors (H1Rs) are endothelial sensors of fluid shear stress and contribute to flow-induced vasodilation. At the molecular level, we observe that H1Rs undergo stimulus-specific patterns of conformational changes suggesting that mechanical forces and agonists induce distinct active receptor conformations. GPCRs lacking C-terminal helix 8 (H8) are not mechanosensitive, and transfer of H8 to non-responsive GPCRs confers, while removal of H8 precludes, mechanosensitivity. Moreover, disrupting H8 structural integrity by amino acid exchanges impairs mechanosensitivity. Altogether, H8 is the essential structural motif endowing GPCRs with mechanosensitivity. These findings provide a mechanistic basis for a better understanding of the roles of mechanosensitive GPCRs in (patho)physiology.


Assuntos
Membrana Celular/fisiologia , Mecanotransdução Celular/fisiologia , Receptores Histamínicos H1/ultraestrutura , Animais , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Técnicas de Silenciamento de Genes , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Knockout , Músculo Liso/citologia , Músculo Liso/fisiologia , Mutagênese Sítio-Dirigida , Miografia , Conformação Proteica em alfa-Hélice/fisiologia , Receptores Histamínicos H1/fisiologia , Estresse Mecânico
17.
Int J Mol Sci ; 20(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775339

RESUMO

Olive leaf extract (OLE) can be obtained as biowaste and is extensively used a food supplement and an over-the-counter drug for its beneficial effects. New studies have investigated OLE concerning the role of oxidative stress in the pathogenesis of vascular disease. This in vitro study aims to evaluate if OLE extracted from the Tuscan Olea europaea protects endothelial cells against oxidative stress generated by reactive oxygen species (ROS). METHODS: OLE total polyphenols (TPs) were characterized by the Folin-Ciocalteu method. Endothelial cells were grown in conventional cultures (i.e., two-dimensional, 2D) and on a biomaterial scaffold (i.e., three-dimensional, 3D) fabricated via electrospinning. Cell viability and ROS measurement after H2O2 insults were performed. RESULTS: OLE TP content was 23.29 mg GAE/g, and oleuropein was the principal compound. The dose-dependent viability curve highlighted the absence of significant cytotoxic effects at OLE concentrations below 250 µg/mL TPs. By using OLE preconditioning at 100 µg/mL, cell viability decrease was observed, being in 3D lower than in the 2D model. OLE was protective against ROS in both models. CONCLUSIONS: OLE represents a high-value antioxidant source obtained by biowaste that is interesting for biomedical products. Using a 3D scaffold could be the best predictive model to mimic the physiological conditions of vascular tissue reaction.


Assuntos
Antioxidantes/farmacologia , Endotélio Vascular/efeitos dos fármacos , Olea/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Substâncias Protetoras/farmacologia , Sobrevivência Celular , Endotélio Vascular/citologia , Humanos , Espécies Reativas de Oxigênio/metabolismo
18.
Int J Mol Sci ; 20(22)2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31744135

RESUMO

Atherosclerosis is one of the most reported diseases worldwide, and extensive research and trials are focused on the discovery and utilizing for novel therapeutics. Nitric oxide (NO) is produced mainly by endothelial nitric oxide synthase (eNOS) and it plays a key role in regulating vascular function including systemic blood pressure and vascular inflammation in vascular endothelium. In this study hypothesized that Impressic acid (IPA), a component isolated from Acanthopanax koreanum, acts as an enhancer of eNOS activity and NO production. IPA treatment induced eNOS phosphorylation and NO production, which was correlated with eNOS phosphorylation via the activation of JNK1/2, p38 MAPK, AMPK, and CaMKII. In addition, the induction of eNOS phosphorylation by IPA was attenuated by pharmacological inhibitor of MAPKs, AMPK, and CaMKII. Finally, IPA treatment prevented the adhesion of TNF-α-induced monocytes to endothelial cells and suppressed the TNF-α-stimulated ICAM-1 expression via activation of NF-κB, while treatment with L-NAME, the NOS inhibitor, reversed the inhibitory effect of IPA on TNF-α-induced ICAM-1 expression via activation of NF-κB. Taken together, these findings show that IPA protects against TNF-α-induced vascular endothelium dysfunction through attenuation of the NF-κB pathway by activating eNOS/NO pathway in endothelial cells.


Assuntos
Eleutherococcus/química , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Eleutherococcus/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , NF-kappa B/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Triterpenos/química
19.
Integr Biol (Camb) ; 11(1): 26-35, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31584068

RESUMO

The hypoxic microenvironment existing in vivo is known to significantly affect cell morphology and dynamics, and cell group behaviour. Collective migration of vascular endothelial cells is essential for vasculogenesis and angiogenesis, and for maintenance of monolayer integrity. Although hypoxic stress increases vascular endothelial permeability, the changes in collective migration and intracellular junction morphology of vascular endothelial cells remain poorly understood. This study reveals the migration of confluent vascular endothelial cells and changes in their adherens junction, as reflected by changes in the vascular endothelial (VE)-cadherin distribution, under hypoxic exposure. Vascular endothelial monolayers of human umbilical vein endothelial cells (HUVECs) were formed in microfluidic devices with controllability of oxygen tension. The oxygen tension was set to either normoxia (21% O2) or hypoxia (<3% O2) by supplying gas mixtures into separate gas channels. The migration velocity of HUVECs was measured using particle image velocimetry with a time series of phase-contrast microscopic images of the vascular endothelial monolayers. Hypoxia inducible factor-1α (HIF-1α) and VE-cadherin in HUVECs were observed after exposure to normoxic or hypoxic conditions using immunofluorescence staining and quantitative confocal image analysis. Changes in the migration speed of HUVECs were observed in as little as one hour after exposure to hypoxic condition, showing that the migration speed was increased 1.4-fold under hypoxia compared to that under normoxia. Nuclear translocation of HIF-1α peaked after the hypoxic gas mixture was supplied for 2 h. VE-cadherin expression was also found to be reduced. When ethanol was added to the cell culture medium, cell migration increased. By contrast, by strengthening VE-cadherin junctions with forskolin, cell migration decreased gradually in spite the effect of ethanol to stimulate migration. These results indicate that the increase of cell migration by hypoxic exposure was attributable to loosening of intercellular junction resulting from the decrease of VE-cadherin expression.


Assuntos
Junções Aderentes/metabolismo , Hipóxia Celular , Movimento Celular , Células Endoteliais da Veia Umbilical Humana/citologia , Transporte Ativo do Núcleo Celular , Antígenos CD/metabolismo , Caderinas/metabolismo , Colforsina/farmacologia , Endotélio Vascular/citologia , Etanol/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Processamento de Imagem Assistida por Computador , Junções Intercelulares/metabolismo , Dispositivos Lab-On-A-Chip , Microfluídica , Microscopia de Contraste de Fase , Oxigênio/metabolismo
20.
Electrophoresis ; 40(23-24): 3108-3116, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31650569

RESUMO

Accurate profiling of the lipophilicity of amphoteric compounds might be complex and laborious. In the present work the lipophilicity of 12 anthracycline antibiotics-four parent drugs: doxorubicin, daunorubicin, epidoxorubicin, and epidaunorubicin and eight novel formamidyne derivatives with attached morpholine, hexamethylenoimine or piperidine rings-was determined based on novel approach using MEEKC. In the second stage, lipophilicity was correlated with anthracycline toxicity towards two cell lines. In rat cardiomyoblast cell line (h9c2) a significant correlation between the logP and toxicity was found. The anthracycline lipophilicity was not correlated with toxicity towards the endothelial hybrid cell line (EAhy.926). In conclusion, the lipophilicity of anthracyclines seems to determine their toxicity towards cardiomyoblasts but not on endothelial cells, suggesting a different mechanism of anthracyclines intercellular transport or extrusion in cardiomyoblast and endothelial cells.


Assuntos
Antraciclinas , Antibacterianos , Cardiotoxinas , Cromatografia Capilar Eletrocinética Micelar/métodos , Animais , Antraciclinas/análise , Antraciclinas/química , Antraciclinas/toxicidade , Antibacterianos/análise , Antibacterianos/química , Antibacterianos/toxicidade , Cardiotoxinas/análise , Cardiotoxinas/química , Cardiotoxinas/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Interações Hidrofóbicas e Hidrofílicas , Ratos
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