Hirudin prevents vascular endothelial cell apoptosis and permeability enhancement induced by the serum from rat with chronic renal failure through inhibiting <scp>RhoA</scp>/<scp>ROCK</scp> signaling pathway

Chen, Jing; Shi, Wenbin; Xu, Yi; Zhang, Huaming; Chen, Bin

doi:10.1002/ddr.21773

Cited by 12 publications

(13 citation statements)

References 35 publications

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“…Animal experiments were performed as previously described ( 23 ). A total of 40 male Wistar rats (age, 6-7 weeks; weight, 160-180 g) were obtained from Nanjing Jiancheng Bioengineering Institute, and maintained in a 12 h light/dark cycle, with 50-60% humidity at 22-26˚C.…”

Section: Methodsmentioning

confidence: 99%

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Hydroxysafflor Yellow A inhibits the viability and migration of vascular smooth muscle cells induced by serum from rats with chronic renal failure via inactivation of the PI3K/Akt signaling pathway

Huo¹,

Wang²,

Wang³

et al. 2021

Exp Ther Med

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It has been reported that the viability and migration of vascular smooth muscle cells contributes to arteriovenous fistula stenosis. Hydroxysafflor Yellow A (HSYA) has been demonstrated to inhibit the viability and migration of VSMCs by regulating Akt signaling. The present study aimed to investigate the role of HSYA on the viability and migration of human umbilical vein smooth muscle cells (HUVSMCs) following stimulation using serum from rats with chronic renal failure (CRF), and to determine the effects of HSYA on PI3K/Akt signaling. Wistar rats were randomly divided into two groups, control and CRF groups. Serum from each group was collected to stimulate the HUVSMCs. Cell Counting Kit-8 and wound healing assays were performed to assess cell viability and migration, respectively. Flow cytometry analysis was performed to assess apoptosis, and western blot analysis was performed to detect protein expression levels of PI3K and Akt. Nitric oxide (NO) production was measured using the Nitrate/Nitrite assay kit. The results demonstrated that serum from CRF rats significantly enhanced cell viability, migration and apoptosis, the effects of which were reversed following treatment with HSYA. In addition, CRF serum decreased NO and endothelial NO synthase expression, whilst increasing the protein expression levels of PI3K and phosphorylated-Akt in HUVSMCs. Notably, treatment with HSYA markedly restored NO production and inactivated the PI3K/Akt signaling pathway. Furthermore, the PI3K/Akt inhibitor, AMG511, exerted similar effects to HSYA. Taken together, the results of the present study suggest that HSYA suppresses cell viability and migration in the presence of CRF serum by inactivating the PI3K/Akt signaling pathway.

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Section: Methodsmentioning

confidence: 99%

“…All experiments were performed as previously described ( 23-26 ). Blood samples were centrifuged at 1,000 x g for 10 min to collect serum.…”

Section: Methodsmentioning

confidence: 99%

Hydroxysafflor Yellow A inhibits the viability and migration of vascular smooth muscle cells induced by serum from rats with chronic renal failure via inactivation of the PI3K/Akt signaling pathway

Huo¹,

Wang²,

Wang³

et al. 2021

Exp Ther Med

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“…Hirudin is a promising anticoagulant drug, a large number of studies have indicated that hirudin has the functions of inhibiting platelet aggregation, reducing blood lipids, regressing atherosclerosis, promoting the absorption of cerebral hematoma, and relieving intracranial pressure ( Azzopardi et al, 2011 ; Bian et al, 2020 ; Junren et al, 2021 ; Nilius et al, 2021 ). In the treatment of cardiovascular diseases, the roles of hirudin in reducing inflammatory infiltration of vascular tissue, inhibiting the proliferation of vascular smooth muscle cells, improving endothelial dysfunction, regulating autophagy levels, resisting oxidative damage, and accelerating lipid metabolism have been gradually revealed ( Dong et al, 2016 ; Yu et al, 2018 ; Wang et al, 2019 ; Zhang H. et al, 2020 ; Chen et al, 2021 ). However, the mechanism by which hirudin improves myocardial hypertrophy remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Network Pharmacology and In Vitro Experimental Verification Reveal the Mechanism of the Hirudin in Suppressing Myocardial Hypertrophy

et al. 2022

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Background: Myocardial hypertrophy is a complex pathological process, which is a common manifestation during the development of various cardiovascular diseases. Hirudin has been shown to have therapeutic effects on a variety of cardiovascular diseases, however, its therapeutic effect on myocardial hypertrophy is still unknown, and its chemical and pharmacological characteristics remain to be elucidated.Methods: In this study, the network pharmacology method was used to characterize the mechanism of hirudin on myocardial hypertrophy. The potential protein targets of hirudin and myocardial hypertrophy were both obtained from the Genecards database, and potential pathways associated with genes were identified by Gene Ontology and pathway enrichment analysis, and the data were displayed in a visual manner. Subsequently, the potential mechanism of action of hirudin on myocardial hypertrophy predicted by network pharmacology analysis was verified by molecular docking, and finally, the main findings were further verified by in vitro experiments by molecular biology techniques. Based on the results obtained from the study of H9c2 cell line, the inhibitory effect of hirudin on myocardial hypertrophy was further proved in the primary rat cardiomyocytes.Results: A total of 250 targets of hirudin, and 5,376 targets related to myocardial hypertrophy after deduplication were collected. The drug-disease network showed the relationship between hirudin, myocardial hypertrophy, and the targets. Further, systematic analysis from the PPI network indicated that blood coagulation, vesicle lumen, and signaling receptor activator activity may be the potential mechanisms of hirudin in the treatment of myocardial hypertrophy, and the PI3K/AKT signaling pathway may be the most relevant to the therapeutic effect of hirudin. Then, three therapeutic targets that were highly related to myocardial hypertrophy were extracted. Hirudin can be highly bound to STAT3, IL-6, and MAPK1 and found by molecular docking, which may be the basis for its inhibitory effect on myocardial hypertrophy. In addition, in vitro experiments showed that hirudin could inhibit AngII-induced hypertrophy and death of H9c2 cells, and significantly reduce the mRNA and protein expression levels of STAT3, MAPK1, and IL-6. The above conclusions were verified in primary rat cardiomyocytes.Conclusion: Hirudin can be used to treat myocardial hypertrophy through a complex mechanism. The application of network pharmacology and experimental validation can promote the application of hirudin in cardiovascular diseases and the interpretation and understanding of molecular biological mechanisms.

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“…In the past years, accelerated programmed cell death or apoptosis has been demonstrated among patients with chronic renal failure (CRF) which may be caused by uremic toxins ( Chen et al, 2021 ). An increased Fas ligand (FasL, a 40-kd type II integral membrane protein) level in ESRD patients has been reported which is a key regulatory apoptotic pathway of the cell death ( Perianayagam et al, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

Baseline Ratio of Soluble Fas/FasL Predicts Onset of Pulmonary Hypertension in Elder Patients Undergoing Maintenance Hemodialysis: A Prospective Cohort Study

et al. 2022

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BackgroundPulmonary hypertension (PH) is one of the most common complications associated with end-stage renal disease (ESRD). Though numerous risk factors have been founded, other risk factors remain unidentified, particularly in patients undergoing maintenance hemodialysis with elder age. Soluble Fas (sFas) and its ligand FasL (sFasL) have been reported in chronic renal disease patients; however, they have not been identified in the PH patients of elder hemodialysis patients. We aimed to determine the roles of sFas/sFasL in onset of PH in elder patients undergoing maintenance hemodialysis with ESRD.MethodsAltogether, 163 patients aged 68.00 ± 10.51 years with ESRD who undergoing maintenance hemodialysis in a prospective cohort and were followed-up for a median of 5.5 years. They underwent echocardiography examinations, liver function assessments, residual renal function, and serum ion examinations, before and after dialysis. Furthermore, levels of sFas and sFasL at baseline had also been measured. We compared demographic data, echocardiographic parameters, liver function, ions, and residual renal function as well as serum sFas and sFasL between the PH and non-PH groups. These parameters were correlated with systolic pulmonary artery pressure (sPAP) using Spearman’s correlation. Moreover, univariate and adjusted logistic regression analyses have also been conducted.ResultsThe incidence of PH in the elder dialysis patients was 39.1%. PH populations were demonstrated with significantly higher end-diastolic internal diameters of the left atrium, left ventricle, right ventricle (RV), and pulmonary artery, as well as the left ventricular posterior wall thickness (LVWP; all p < 0.05). A higher baseline serum sFas and sFasL levels have also been identified ( p < 0.001). They also showed lower fractional shortening and left ventricular ejection fraction (LVEF; p < 0.05). Following dialysis, the post-dialysis serum potassium concentration (K+) was significantly higher in the PH group ( p = 0.013). Furthermore, the adjusted regression identified that ratio of sFas/FasL (OR: 1.587, p = 0.004), RV (OR: 1.184, p = 0.014), LVPW (OR: 1.517, p = 0.007), and post-dialysis K+ (OR: 2.717, p = 0.040) was the independent risk factors for PH while LVEF (OR: 0.875, p = 0.040) protects patients from PH.ConclusionThe baseline ratio of sFas/sFasL, RV, LVPW, and post-dialysis K+ was independent risk factors for PH onset, while LVEF was a protective factor for PH.

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Hirudin prevents vascular endothelial cell apoptosis and permeability enhancement induced by the serum from rat with chronic renal failure through inhibiting RhoA/ROCK signaling pathway

Cited by 12 publications

References 35 publications

Hydroxysafflor Yellow A inhibits the viability and migration of vascular smooth muscle cells induced by serum from rats with chronic renal failure via inactivation of the PI3K/Akt signaling pathway

Hydroxysafflor Yellow A inhibits the viability and migration of vascular smooth muscle cells induced by serum from rats with chronic renal failure via inactivation of the PI3K/Akt signaling pathway

Network Pharmacology and In Vitro Experimental Verification Reveal the Mechanism of the Hirudin in Suppressing Myocardial Hypertrophy

Baseline Ratio of Soluble Fas/FasL Predicts Onset of Pulmonary Hypertension in Elder Patients Undergoing Maintenance Hemodialysis: A Prospective Cohort Study

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