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1.
An Pediatr (Engl Ed) ; 95(6): 406-412, 2021 Dec.
Article En | MEDLINE | ID: mdl-34895646

INTRODUCTION: Primary nephrotic syndrome (NS) is a common glomerular disease in children. We assessed the genotypes and frequency of the rs5370 allelic variant of the EDN1 gene in children with primary NS. PATIENTS AND METHODS: We conducted a case-control study in Mansoura University Children's Hospital, Egypt between December 2015 and January 2018. We recruited 50 patients with steroid-sensitive NS (SSNS) and 50 patients with steroid-resistant NS (SRNS) in addition to 100 healthy controls. The patients underwent clinical evaluations and tests including measurement of serum albumin, cholesterol, creatinine and urea levels and a 24-h urinary protein test. We used polymerase chain reaction methods to assess the genotypes of rs5370 variants of the EDN1 gene (GG, GT and TT) and alleles (T and G) in the groups under study. RESULTS: The most frequent genotype of the EDN1 gene at the locus of interest in the control group was the GT genotype (88%; P=.001) while the GG genotype was more frequent in the NS group compared to the control group (P=.02). We did not find statistically significant differences between the NS and control groups in regard to the EDN1 rs5370 alleles (P=.69). The GG genotype was more frequent in the SSNS group compared to the SRNS and control groups (P=.03). When we compared allele frequencies between the control, SSNS and SRNS groups, we did not find significant differences (P=.89). The GT genotype was associated with normal blood pressure in children with NS (P=.007), while the GG genotype was associated with hypertension (P<.001). We did not find statistically significant differences in renal histopathology or serum cholesterol levels based on the genotype. CONCLUSIONS: The GG genotype at the rs5370 locus of the EDN1 gene may be associated with an increased risk of primary NS and a better response to steroid therapy.


Endothelin-1 , Nephrotic Syndrome , Case-Control Studies , Child , Endothelin-1/genetics , Gene Frequency , Humans , Nephrotic Syndrome/genetics , Polymorphism, Genetic
2.
Int J Mol Sci ; 22(11)2021 Jun 03.
Article En | MEDLINE | ID: mdl-34205035

Hyperpigmentation is a dermatological condition characterized by the overaccumulation and/or oversecretion of melanin pigment. The efficacy of curcumin as an anti-melanogenic therapeutic has been recognized, but the poor stability and solubility that have limited its use have inspired the synthesis of novel curcumin analogs. We have previously reported on comparisons of the anti-melanogenic activity of four novel chemically modified curcumin (CMC) analogs, CMC2.14, CMC2.5, CMC2.23 and CMC2.24, with that of parent curcumin (PC), using a B16F10 mouse melanoma cell model, and we have investigated mechanisms of inhibition. In the current study, we have extended our findings using normal human melanocytes from a darkly pigmented donor (HEMn-DP) and we have begun to study aspects of melanosome export to human keratinocytes. Our results showed that all the CMCs downregulated the protein levels of melanogenic paracrine mediators, endothelin-1 (ET-1) and adrenomedullin (ADM) in HaCaT cells and suppressed the phagocytosis of FluoSphere beads that are considered to be melanosome mimics. All the three CMCs were similarly potent (except CMC2.14, which was highly cytotoxic) in inhibiting melanin production; furthermore, they suppressed dendricity in HEMn-DP cells. CMC2.24 and CMC2.23 robustly suppressed cellular tyrosinase activity but did not alter tyrosinase protein levels, while CMC2.5 did not suppress tyrosinase activity but significantly downregulated tyrosinase protein levels, indicative of a distinctive mode of action for the two structurally related CMCs. Moreover, HEMn-DP cells treated with CMC2.24 or CMC2.23 partially recovered their suppressed tyrosinase activity after cessation of the treatment. All the three CMCs were nontoxic to human dermal fibroblasts while PC was highly cytotoxic. Our results provide a proof-of-principle for the novel use of the CMCs for skin depigmentation, since at low concentrations, ranging from 5 to 25 µM, the CMCs (CMC2.24, CMC2.23 and CMC2.5) were more potent anti-melanogenic agents than PC and tetrahydrocurcumin (THC), both of which were ineffective at melanogenesis at similar doses, as tested in HEMn-DP cells (with PC being highly toxic in dermal fibroblasts and keratinocytes). Further studies to evaluate the efficacy of CMCs in human skin tissue and in vivo studies are warranted.


Curcumin/pharmacology , Hyperpigmentation/drug therapy , Melanins/biosynthesis , Melanoma, Experimental/drug therapy , Adrenomedullin/genetics , Animals , Curcumin/analogs & derivatives , Curcumin/chemistry , Endothelin-1/genetics , Humans , Hyperpigmentation/metabolism , Hyperpigmentation/pathology , Keratinocytes/drug effects , Keratinocytes/metabolism , Melanins/antagonists & inhibitors , Melanocytes/drug effects , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Melanosomes/drug effects , Melanosomes/genetics , Mice , Phagocytosis/genetics , Skin/drug effects , Skin/metabolism , Skin/pathology
3.
J Hypertens ; 39(9): 1908-1917, 2021 09 01.
Article En | MEDLINE | ID: mdl-34039912

OBJECTIVE: Mechanisms of blood pressure (BP) regulation by endothelin (ET)-1 produced by endothelial cells are complex and remain unclear. Long-term exposure to human ET-1 (hET-1) in mice inducibly overexpressing hET-1 in the endothelium (ieET-1) caused sustained BP elevation. ET-1 has been shown to stimulate the release of aldosterone. Whether aldosterone plays a role in hET-1 overexpression-induced BP elevation and vessel injury is unknown. METHOD: Nine- to 12-week-old male ieET-1 mice and control mice expressing a tamoxifen-inducible Cre recombinase (CreERT2) in the endothelial cells (ieCre) were treated with tamoxifen for 5 days and studied 3 months later. RESULTS: Endothelial hET-1 overexpression increased plasma aldosterone levels, which was reversed by 2-week treatment with atrasentan, an endothelin type A receptors blocker. Aldosterone synthase and cryptochrome 2 adrenal cortex mRNA expression was decreased in ieET-1 mice. Two-week treatment with eplerenone, a mineralocorticoid receptor antagonist, reduced systolic BP by 10 mmHg in ieET-1 mice during rest time. Saline challenge-induced sodium excretion and renal cortex thiazide-sensitive sodium-chloride cotransporter mRNA expression were decreased in ieET-1 mice. The sensitivity of mesenteric arteries to contraction by norepinephrine was increased in ieET-1 mice, and was abrogated by eplerenone treatment, whereas sensitivity of endothelium-independent relaxation responses to sodium nitroprusside was enhanced. Resistance artery remodeling was reduced in eplerenone-treated ieET-1 vs. ieET-1 and ieCre mice. CONCLUSION: These results demonstrate that aldosterone contributes to BP elevation and vascular norepinephrine sensitivity and remodeling caused by hET-1 overexpression in endothelium in mice.


Endothelin-1 , Hypertension , Aldosterone , Animals , Endothelial Cells , Endothelin-1/genetics , Endothelium, Vascular , Humans , Hypertension/chemically induced , Hypertension/genetics , Male , Mesenteric Arteries , Mice
4.
J Biomed Sci ; 28(1): 38, 2021 May 19.
Article En | MEDLINE | ID: mdl-34011384

BACKGROUND: Histone deacetylase (HDAC) inhibition was reported to ameliorate lung fibrosis in animal models. However, little is known about the underlying mechanism of HDAC7 in the regulation of CTGF production in lung fibroblasts. METHODS: The role of HDAC7 in CTGF production caused by ET-1 stimulation in WI-38 cells (human lung fibroblast) was examined. We also evaluated the expression of HDAC7 in the lung of ovalbumin-induced airway fibrosis model. Statistical data were shown as mean ± standard error. RESULTS: ET-1-stimulated CTGF and α-SMA expression was attenuated by small interfering (si)RNA interference of HDAC7. ET-1 promoted HDAC7 translocation from the cytosol to nucleus. ET-1-stimulated CTGF expression was reduced by the transfection of p300 siRNA. ET-1 induced an increase in p300 activity. Furthermore, the acetylation of c-Jun was time-dependently induced by ET-1 stimulation, which was reduced by transfection of either HDAC7 or p300 siRNA. Both transfection of HDAC7 and p300 siRNA suppressed the ET-1-increased activity of AP-1-luciferase. Moreover, the presence of HDAC7 was required for ET-1-stimulated formation of HDAC7, p300, and AP-1 complex and recruitment to the CTGF promoter region. In an ovalbumin-induced airway fibrosis model, the protein level of HDAC7 was increased in the lung tissue, and the distribution of HDAC7 was colocalized with α-SMA-positive cells in the subepithelial layer of the airway. CONCLUSIONS: ET-1 activates HDAC7 to initiate AP-1 transcriptional activity by recruiting p300 and eventually promotes the production of CTGF. HDAC7 might play a vital role in airway fibrosis and have the potential to be developed as a therapeutic target.


Connective Tissue Growth Factor/genetics , E1A-Associated p300 Protein/metabolism , Endothelin-1/genetics , Gene Expression , Histone Deacetylases/genetics , Transcription Factor AP-1/metabolism , Cell Line , Connective Tissue Growth Factor/metabolism , Endothelin-1/metabolism , Fibroblasts , Histone Deacetylases/metabolism , Humans , Lung
5.
BMC Res Notes ; 14(1): 194, 2021 May 19.
Article En | MEDLINE | ID: mdl-34011397

OBJECTIVE: Endothelin-1 plays an important role in the pathogenesis of severe pulmonary hypertension. The + 139 'A', adenine insertion variant in 5'UTR of edn1 gene has been reported to be associated with increased expression of Endothelin-1 in vitro. The aim of present study was to explore the association of this variant with the circulating levels of Endothelin-1 in vivo using archived DNA and plasma samples from 38 paediatric congenital heart disease (cyanotic and acyanotic) patients with severe pulmonary hypertension. RESULTS: The plasma Endothelin-1 levels were highly varied ranging from 1.63 to75.16 pg/ml. The + 139 'A' insertion variant in 5'UTR of edn1 was seen in 8 out of 38 cases with only one acyanotic sample demonstrating homozygosity of inserted 'A' allele at + 139 site (4A/4A genotype). The plasma Endothelin-1 levels in children with homozygous variant 3A/3A genotype were comparable in cyanotic and acyanotic groups. Lone 4A/4A acyanotic sample had ET-1 levels similar to the median value of ET-1 associated with 3A/3A genotype and was absent in cyanotic group presumably due to deleterious higher ET-1 levels. The discussed observations, limited by the small sample size, are suggestive of homozygous adenine insertion variant posing a risk in cyanotic babies with Severe Pulmonary Hypertension.


Endothelin-1 , Hypertension, Pulmonary , 5' Untranslated Regions/genetics , Adenine , Child , Endothelin-1/genetics , Humans , Hypertension, Pulmonary/genetics , Mutation
6.
J Urol ; 206(3): 679-687, 2021 09.
Article En | MEDLINE | ID: mdl-33904754

PURPOSE: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence. MATERIALS AND METHODS: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction. RESULTS: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10-8). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure (MARCO) gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 (EDN1) gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001). CONCLUSIONS: We uncovered 2 new risk loci near the genes endothelin 1 (EDN1), associated with urgency incontinence, and macrophage receptor with collagenous structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.


Genetic Loci , Urinary Incontinence, Stress/genetics , Case-Control Studies , Endothelin-1/genetics , Female , Genome-Wide Association Study , Humans , Middle Aged , Polymorphism, Single Nucleotide , Receptors, Immunologic/genetics , /genetics
7.
Protein Pept Lett ; 28(7): 831-840, 2021.
Article En | MEDLINE | ID: mdl-33573539

BACKGROUND: Many fishes have been known for their good nutritional effects especially in the cardiovascular aspect. Some specific fish peptides have anti-hypertensive effects. OBJECTIVE: In the present study, we hypothesized that the hexapeptide (MEVFVP) from flounder fish muscle can be a potent antihypertensive peptide, therefore, decided to perform this experiment. METHODS: The peptide MEVFVP from flounder fish muscle (40 mg/kg) and vehicle were administered per os to spontaneously hypertensive rats (SHRs) (SHR-M and SHR-C, respectively). Additionally, plasma MEVFVP was measured serially before and after its oral administration to Sprague Dawley rats. RESULTS: Blood pressures (BPs), especially systolic BP, in SHR rats were decreased around 3-6 hours after MEVFVP administration. Compared with SHR-C rats, endothelin-1 (ET-1) mRNA expression in multiple tissues, and plasma levels of ET-1, angiotensin II, and aldosterone were lower in SHR-M rats, whereas the phosphorylation of AMP-activated protein kinase (AMPK) was increased in the kidney of SHR-M rats. The administered peptide was not detected in rat plasma, while ex vivo incubation of the peptide in rat plasma caused its rapid degradation within minutes. CONCLUSION: Our results show that the MEVFVP has an antihypertensive effect by regulating renin- angiotensin-aldosterone system, ET-1 and AMPK despite its limited bioavailability.


Antihypertensive Agents/pharmacology , Endothelin-1/genetics , Fish Proteins/pharmacology , Flounder/metabolism , Hypertension/drug therapy , Oligopeptides/pharmacology , Renin-Angiotensin System/drug effects , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Administration, Oral , Aldosterone/metabolism , Amino Acid Sequence , Angiotensin II/genetics , Angiotensin II/metabolism , Animals , Antihypertensive Agents/isolation & purification , Antihypertensive Agents/pharmacokinetics , Blood Pressure/drug effects , Endothelin-1/antagonists & inhibitors , Endothelin-1/metabolism , Fish Proteins/isolation & purification , Fish Proteins/pharmacokinetics , Gene Expression Regulation , Hypertension/genetics , Hypertension/metabolism , Hypertension/physiopathology , Kidney/drug effects , Kidney/metabolism , Kidney/physiopathology , Male , Muscles/chemistry , Oligopeptides/isolation & purification , Oligopeptides/pharmacokinetics , Rats , Rats, Inbred SHR , Rats, Sprague-Dawley , Renin-Angiotensin System/genetics , Signal Transduction
8.
Int J Legal Med ; 135(4): 1499-1506, 2021 Jul.
Article En | MEDLINE | ID: mdl-33559002

BACKGROUND: Both obstructive sleep apnea (OSA) and (at least a fraction of) sudden infant death syndrome (SIDS) are associated with impaired respiration. For OSA, an association with several gene variants was identified. Therefore, our hypothesis is that these polymorphisms might be of relevance in SIDS as well. METHODS: Twenty-four single nucleotide polymorphisms (SNPs) in 21 candidate genes connected to OSA, were genotyped in a total of 282 SIDS cases and 374 controls. Additionally, subgroups based on factors codetermining the SIDS risk (age, sex, season, and prone position) were established and compared as well. RESULTS: Two of the analyzed SNPs showed nominally significant differences between SIDS and control groups: rs1042714 in ADRB2 (adrenoceptor beta 2) and rs1800541 in EDN1 (endothelin 1). In the subgroup analyses, 10 further SNPs gave significant results. Nevertheless, these associations did not survive adjustment for multiple testing. CONCLUSIONS: Our results suggest that there might be a link between SIDS and OSA and its resulting respiratory and cardiovascular problems, albeit this predisposition might be dependent on the combination with other, hitherto unknown gene variants. These findings may encourage replication studies to get a better understanding of this connection.


Polymorphism, Single Nucleotide , Sleep Apnea, Obstructive/genetics , Sudden Infant Death/genetics , Case-Control Studies , Endothelin-1/genetics , Female , Genetic Predisposition to Disease , Genotype , Germany , Humans , Infant , Infant, Newborn , Male , Receptors, Adrenergic, beta-2/genetics
9.
PLoS One ; 16(2): e0246067, 2021.
Article En | MEDLINE | ID: mdl-33539452

Priapism is a urologic emergency characterized by an uncontrolled, persistent and painful erection in the absence of sexual stimulation, which can lead to penile fibrosis and impotence. It is highly frequent in sickle cell disease (SCD) associated with hemolytic episodes. Our aim was to investigate molecules that may participate in the regulation of vascular tone. Eighty eight individuals with SCD were included, of whom thirty-seven reported a history of priapism. Priapism was found to be associated with alterations in laboratory biomarkers, as well as lower levels of HbF. Patients with sickle cell anemia using hydroxyurea and those who received blood products seemed to be less affected by priapism. Multivariate analysis suggested that low HbF and NOm were independently associated with priapism. The frequency of polymorphisms in genes NOS3 and EDN1 was not statistically significant between the studied groups, and the presence of the variant allele was not associated with alterations in NOm and ET-1 levels in patients with SCD. The presence of the variant allele in the polymorphisms investigated did not reveal any influence on the occurrence priapism. Future studies involving larger samples, as well as investigations including patients in priapism crisis, could contribute to an enhanced understanding of the development of priapism in SCD.


Anemia, Sickle Cell/complications , Endothelin-1/genetics , Nitric Oxide Synthase Type III/genetics , Polymorphism, Single Nucleotide , Priapism/genetics , Adolescent , Anemia, Sickle Cell/blood , Anemia, Sickle Cell/genetics , Case-Control Studies , Child , Endothelin-1/blood , Fetal Hemoglobin/metabolism , Genetic Association Studies , Humans , Male , Multivariate Analysis , Nitric Oxide/blood , Nitric Oxide Synthase Type III/blood , Priapism/blood , Priapism/etiology
10.
Vascul Pharmacol ; 138: 106841, 2021 06.
Article En | MEDLINE | ID: mdl-33545365

BACKGROUND: Coronary slow flow (CSF) refers to coronary arteries with no obvious stenosis but have slow coronary flow without effective treatment. The main cause of CSF is endothelial dysfunction. The long non-coding RNA (lncRNA) MALAT1 is involved in regulating endothelial dysfunction, but its role in CSF endothelial dysfunction is still unclear. METHODS: We included 41 CSF patients and 37 controls in the study, who all underwent coronary angiography, echocardiography, and brachial artery flow-mediated dilatation (FMD) examination. Human umbilical vein endothelial cells (HUVECs) stimulated by oxygen-glucose deprivation were used as CSF-induced HUVECs. Plasma endothelin-1 (ET-1) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). The expression levels of MALAT1, miR-181b-5p, myocyte enhancer factor 2A (MEF2A), and ET-1 were measured by qRT-PCR or western blotting. Cell proliferation was determined by 5-ethynyl-2'-deoxyuridine (EdU) and Cell Counting Kit-8 (CCK-8) assays. Apoptosis was examined by flow cytometry. The relationship between miR-181b-5p and MALAT1 or MEF2A was verified by dual-luciferase reporter assay. MEF2A binding directly to the ET-1 promoter region was verified via chromatin immunoprecipitation (ChIP) assay. RESULTS: MALAT1 and ET-1 were increased, and miR-181b-5p was decreased in the peripheral blood of the CSF patients, and could be used as predictors of CSF. In the CSF-induced HUVECs, MALAT1 was highly expressed, and MALAT1 knockdown improved endothelial function. In contrast, miR-181b-5p was downregulated in the CSF-induced HUVECs, and miR-181b-5p overexpression improved endothelial function. While MEF2A was highly enriched in CSF-induced HUVECs, MEF2A knockdown reduced ET-1 and increased the endothelial function of CSF-induced HUVECs as a transcriptional regulator of ET-1. MALAT1 modulated MEF2A expression positively by sponging miR-181b-5p. CONCLUSIONS: Endothelial function is reduced in CSF. MALAT1 participates in regulating CSF endothelial dysfunction through the miR-181b-5p-MEF2A-ET-1 axis, and could provide a new target for CSF treatment.


Coronary Artery Disease/metabolism , Coronary Vessels/metabolism , Endothelin-1/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , Aged , Blood Flow Velocity , Case-Control Studies , Cells, Cultured , Coronary Artery Disease/genetics , Coronary Artery Disease/physiopathology , Coronary Circulation , Coronary Vessels/physiopathology , Endothelin-1/genetics , Female , Humans , MEF2 Transcription Factors/genetics , MEF2 Transcription Factors/metabolism , Male , MicroRNAs/genetics , Middle Aged , RNA, Long Noncoding/genetics , Signal Transduction
11.
Exp Neurol ; 337: 113596, 2021 03.
Article En | MEDLINE | ID: mdl-33417892

Subarachnoid haemorrhage (SAH) is a devastating cerebrovascular disease which has a high morbidity and mortality. The phenotypic transformation of smooth muscle cells (SMCs) lead to neurovascular injury after SAH. However, the underlying mechanism remains unclear. In the present study, we aimed to investigate the potential role of ET-1/ETAR on the phenotypic transformation of SMCs after SAH. The models of SAH were established in vivo and vitro. We observed ET-1 secretion by endothelial cells was increased, and the phenotypic transformation of SMCs was aggravated after SAH. Knocking down ETAR inhibited the phenotypic transformation of SMCs, decreased the migration ability of SMCs in vitro. Moreover, Knocking down ETAR ameliorated cerebral ischaemia and alleviated dysfunction of neurological function in vivo. In addition, Exogenous ET-1 increased the migration ability of SMCs and aggravated the phenotypic transformation of SMCs in vitro, which were partly reversed by the antagonist of Erk1/2 - SCH772984. Taken together, our results demonstrated that endothelial ET-1 aggravated the phenotypic transformation of SMCs after SAH. Knocking down ETAR inhibited the phenotypic transformation of SMCs through ERK/KLF4 thus ameliorating neurovascular injury after SAH. We also revealed that ET-1/ETAR is a potential therapeutic target after SAH.


Kruppel-Like Transcription Factors/genetics , MAP Kinase Signaling System/genetics , Myocytes, Smooth Muscle/pathology , Receptors, Endothelin/genetics , Subarachnoid Hemorrhage/genetics , Animals , Animals, Genetically Modified , Cell Movement , Cerebrovascular Circulation , Endothelial Cells/metabolism , Endothelin-1/genetics , Gene Knockdown Techniques , Humans , MAP Kinase Signaling System/drug effects , Male , Phenotype , RNA, Small Interfering/genetics , Rats , Rats, Sprague-Dawley , Receptor, Endothelin A , Subarachnoid Hemorrhage/pathology
12.
Anticancer Res ; 41(1): 169-174, 2021 Jan.
Article En | MEDLINE | ID: mdl-33419810

BACKGROUND/AIM: Vimentin3 (Vim3) was recently described as a tumour marker for the direct discrimination between benign and malignant kidney tumours. Here, we examined its expression in prostate cancer (PCa) cell lines and the regulation of its expression by endothelin receptors. MATERIALS AND METHODS: Prostate cancer cell lines (PC3, DU145, LNCap) were incubated with endothelin 1 (ET-1), BQ123 [endothelin A receptor (ETAR) antagonist], BQ788 [endothelin B receptor (ETBR) antagonist], BQ123+ET-1, BQ788+ET-1 for 24 h and a scratch assay was performed. Cell extracts were analysed by western blotting and qRT-PCR. RESULTS: ET-1 induced Vim3 overexpression. Blocking the ETBR in the different prostate cancer cell lines yielded a higher migration rate, whereby Vim3 expression was significantly increased. CONCLUSION: Vim3 concentration increases in cell lines without a functional ETBR and may be used as a marker for PCas where ETBR is frequently methylated.


Gene Expression , Prostatic Neoplasms/genetics , Vimentin/genetics , Biomarkers, Tumor , Cell Line, Tumor , Cell Movement , Cells, Cultured , Endothelin-1/genetics , Endothelin-1/metabolism , Humans , Male , Prostatic Neoplasms/metabolism
13.
Gene ; 775: 145428, 2021 Apr 05.
Article En | MEDLINE | ID: mdl-33460763

BACKGROUND: Myocardial infarction (MI) and underlining atherosclerosis are the main causes of death worldwide. Phosphatase and actin regulator 1 (PHACTR1) variants have been associated with early onset MI, coronary artery disease and carotid dissection. PHACTR1 mRNA expression has been detected in tissues and cells related to atherosclerosis. Nonetheless, the true effect of PHACTR1 on vascular diseases is still unknown. Our aim was to examine the association of PHACTR1 intronic variants, rs9349379, rs2026458 and rs2876300, with MI and multi-vessel disease (MVD) and to assess their effect on PHACTR1 and EDN1 mRNA expression in PBMCs of patients six months after MI. METHODS: The study enrolled 537 patients with the first MI and 310 controls. Gene expression was assessed in 74 patients six months after MI and 37 healthy controls. Rs9349379, rs2026458, rs2876300 and relative mRNA expressions were detected by TaqMan® technology. RESULTS: The significant association between PHACTR1 variants and MI was not found, either individually or in haplotype. A higher frequency of rs2876300G-allele in MVD was rendered not significant after Bonferroni correction. PHACTR1 mRNA was significantly increased in PBMCs of patients six months after MI compared to controls (p = 0.02). Patients that carry ACG haplotype have increased PHACTR1 mRNA expression in PBMCs (p = 0.04). There was no effect of PHACTR1 variants on EDN1 mRNA expression. CONCLUSION: Our findings suggest that PHACTR1 intronic variants may have a role in severity and progression of coronary atherosclerosis. Future research is needed to clarify the mechanism underlying the role of PHACTR1 in coronary atherosclerosis and MI.


Microfilament Proteins/genetics , Myocardial Infarction/genetics , Polymorphism, Single Nucleotide , Up-Regulation , Adult , Age of Onset , Aged , Case-Control Studies , Endothelin-1/genetics , Female , Genetic Association Studies , Humans , Introns , Male , Middle Aged , Severity of Illness Index
14.
Am J Physiol Heart Circ Physiol ; 320(3): H1021-H1036, 2021 03 01.
Article En | MEDLINE | ID: mdl-33481696

Pulmonary hypertension (PH) causes cardiac hypertrophy in the right ventricle (RV) and eventually leads to RV failure due to persistently elevated ventricular afterload. We hypothesized that the mechanical stress on the RV associated with increased afterload impairs vasodilator function of the right coronary artery (RCA) in PH. Coronary vascular response was assessed using microangiography with synchrotron radiation (SR) in two well-established PH rat models, monocrotaline injection or the combined exposure to chronic hypoxia and vascular endothelial growth factor receptor blockade with Su5416 (SuHx model). In the SuHx model, the effect of the treatment with the nonselective endothelin-1 receptor antagonist (ERA), macitentan, was also examined. Myocardial viability was determined in SuHx model rats, using 18F-FDG Positron emission tomography (PET) and magnetic resonance imaging (MRI). Endothelium-dependent and endothelium-independent vasodilator responses were significantly attenuated in the medium and small arteries of severe PH rats. ERA treatment significantly improved RCA vascular function compared with the untreated group. ERA treatment improved both the decrease in ejection fraction and the increased glucose uptake, and reduced RV remodeling. In addition, the upregulation of inflammatory genes in the RV was almost suppressed by ERA treatment. We found impairment of vasodilator responses in the RCA of severe PH rat models. Endothelin-1 activation in the RCA plays a major role in impaired vascular function in PH rats and is partially restored by ERA treatment. Treatment of PH with ERA may improve RV function in part by indirectly attenuating right heart afterload and in part by associated improvements in right coronary endothelial function.NEW & NOTEWORTHY We demonstrated for the first time the impairment of vascular responses in the right coronary artery (RCA) of the dysfunctional right heart in pulmonary hypertensive rats in vivo. Treatment with an endothelin-1 receptor antagonist ameliorated vascular dysfunction in the RCA, enabled tissue remodeling of the right heart, and improved cardiac function. Our results suggest that impaired RCA function might also contribute to the early progression to heart failure in patients with severe pulmonary arterial hypertension (PAH). The endothelium of the coronary vasculature might be considered as a potential target in treatments to prevent heart failure in severe patients with PAH.


Coronary Angiography , Coronary Vessels/diagnostic imaging , Hypertrophy, Right Ventricular/diagnostic imaging , Pulmonary Arterial Hypertension/diagnostic imaging , Synchrotrons , Vasodilation , Ventricular Dysfunction, Right/diagnostic imaging , Animals , Antihypertensive Agents/pharmacology , Coronary Vessels/drug effects , Coronary Vessels/metabolism , Coronary Vessels/physiopathology , Disease Models, Animal , Endothelin Receptor Antagonists/pharmacology , Endothelin-1/genetics , Endothelin-1/metabolism , Hypertrophy, Right Ventricular/drug therapy , Hypertrophy, Right Ventricular/metabolism , Hypertrophy, Right Ventricular/physiopathology , Hypoxia/complications , Indoles , Monocrotaline , Predictive Value of Tests , Pulmonary Arterial Hypertension/drug therapy , Pulmonary Arterial Hypertension/metabolism , Pulmonary Arterial Hypertension/physiopathology , Pyrimidines/pharmacology , Pyrroles , Rats, Sprague-Dawley , Severity of Illness Index , Sulfonamides/pharmacology , Vasodilation/drug effects , Ventricular Dysfunction, Right/drug therapy , Ventricular Dysfunction, Right/metabolism , Ventricular Dysfunction, Right/physiopathology , Ventricular Function, Right , Ventricular Remodeling
15.
Life Sci ; 264: 118727, 2021 Jan 01.
Article En | MEDLINE | ID: mdl-33221345

Hypertension is one of the most prevalent diseases worldwide. Increased synthesis of the vasoconstrictor peptide endothelin 1 (encoded by EDN1) might be responsible for high blood pressure. The present study further confirmed the abnormal EDN1 upregulation within adipose tissue-derived stromal cells (ADSCs) derived from morbidly obese subjects. The overexpression of EDN1 in ADSCs derived from non-obese subjects significantly promoted the proliferation and migration of HUVECs and tube formation by human umbilical vein endothelial cell (HUVEC). Transcription factor NR4A3 was positively correlated with EDN1, binding to EDN1 promoter region to upregulate EDN1 expression. Similarly, the overexpression of NR4A3 in ADSCs derived from non-obese subjects significantly promoted the proliferation and migration of HUVECs and tube formation by HUVECs, as well as EDN1 protein levels in ADSCs. However, the effects of NR4A3 overexpression on EDN1 protein levels in ADSCs and the proliferation and migration of HUVECs and tube formation by HUVECs were significantly reversed by EDN1 silencing in ADSCs. In conclusion, NR4A3 is abnormally upregulated in ADSCs derived from morbidly obese subjects; NR4A3 could promote HUVEC angiogenesis through binding to EDN1 promoter and upregulating EDN1 expression.


Adipose Tissue/pathology , DNA-Binding Proteins/metabolism , Endothelin-1/genetics , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/pathology , Receptors, Steroid/metabolism , Receptors, Thyroid Hormone/metabolism , Up-Regulation/genetics , Cell Survival , Endothelin-1/metabolism , Humans , Neovascularization, Physiologic/genetics , Obesity, Morbid/genetics , Promoter Regions, Genetic/genetics , Protein Binding/genetics , Stromal Cells/metabolism
16.
Exp Cell Res ; 399(1): 112443, 2021 02 01.
Article En | MEDLINE | ID: mdl-33340492

The hallmark of atherogenesis is characterized as endothelial dysfunction and subsequent macrophage activation. Although our previous study has demonstrated that endothelin-1 (ET-1) plays an important role in atherogenesis, the underlying mechanism remains deeply investigation. Enhanced atherosclerotic plaques were observed in endothelium-specific ET-1 overexpression ApoE-/- mice (eET-1/ApoE-/-) concomitant with increased secretion of pro-inflammatory adhesion molecules and cytokines. The conditional media used for culturing human umbilical vein endothelial cells (HUVECs) with AdET-1 infection and subjected to OX-LDL stimulation, was collected and utilized for bone marrow-derived macrophages (BMDMs) culturing. RT-PCR analysis showed increased genes expression related to classical M1 macrophages but decreased alternative activated M2 macrophages genes expression in macrophage culturing with the conditional media. Furthermore, consistent regulations of macrophage polarization were observed using isolated exosomes from the conditional media. More importantly, we noticed that miR-33 was enriched in the exosomes derived by HUVECs with AdET-1 infection, while bioinformatics analysis further indicated that miR-33 directly targeted NR4A and miR-33/NR4A axis was required for the effect of endothelial-specific ET-1 overexpression on pro-inflammatory macrophage activation. By contrast, such effects could be reversed by ET-1 knockdown. Taken together, our study indicated that the exosomes derived by HUVECs with AdET-1 infection can transfer miR-33 to macrophages and subsequently promote pro-inflammatory macrophage activation by directly targeting to NR4A. These evidences clearly revealed that miR-33/NR4A axis was the important mechanism underlying the effect of ET-1 on macrophage activation and indicated that ET-1 may act as a promising target for atherosclerosis management.


Endothelin-1/genetics , Endothelium, Vascular/metabolism , Macrophage Activation/genetics , MicroRNAs/genetics , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , Animals , Cells, Cultured , Embryo, Mammalian , Endothelin-1/metabolism , HEK293 Cells , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Macrophages/metabolism , Macrophages/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , MicroRNAs/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , Organ Specificity/genetics , Signal Transduction/genetics
17.
Ann Neurol ; 89(3): 459-473, 2021 03.
Article En | MEDLINE | ID: mdl-33314303

OBJECTIVE: The purpose of this study was to investigate the significance of circulating micro RNAs (miRNAs) in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS). METHODS: We prospectively recruited 3 independent cohorts of patients with RCVS and age-matched and sex-matched controls in a single medical center. Next-generation small RNA sequencing followed by quantitative polymerase chain reaction (PCR) was used to identify and validate differentially expressed miRNAs, which was cross-validated in migraine patients in ictal stage or interictal stage. Computational analysis was used to predict the target genes of miRNAs, followed by in vitro functional analysis. RESULTS: We identified a panel of miRNAs including miR-130a-3p, miR-130b-3p, let-7a-5p, let-7b-5p, and let-7f-5p that well differentiated patients with RCVS from controls (area under the receiver operating characteristics curve [AUC] was 0.906, 0.890, and 0.867 in the 3 cohorts, respectively). The abundance of let-7a-5p, let-7b-5p, and let-7f-5p, but not miR-130a-3p nor miR-130b-3p, was significantly higher in patients with ictal migraine compared with that of controls and patients with interictal migraine. Target prediction and pathway enrichment analysis suggested that the transforming growth factor-ß signaling pathway and endothelin-1 responsible for vasomotor control might link these miRNAs to RCVS pathogenesis, which was confirmed in vitro by transfecting miRNAs mimics or incubating the patients' cerebrospinal fluid (CSF) in 3 different vascular endothelial cells. Moreover, miR-130a-3p was associated with imaging-proven disruption of the blood-brain barrier (BBB) in patients with RCVS and its overexpression led to reduced transendothelial electrical resistance (ie, increased permeability) in in vitro human BBB model. INTERPRETATION: We identified the circulating miRNA signatures associated with RCVS, which may be functionally linked to its headache, BBB integrity, and vasomotor function. ANN NEUROL 2021;89:459-473.


Blood-Brain Barrier/physiopathology , Cerebrovascular Disorders/genetics , Circulating MicroRNA/blood , Endothelial Cells , MicroRNAs/blood , Vasoconstriction/genetics , Adult , Capillary Permeability , Case-Control Studies , Cerebrovascular Disorders/blood , Cerebrovascular Disorders/physiopathology , Circulating MicroRNA/genetics , Computer Simulation , Electric Impedance , Endothelin-1/genetics , Endothelin-1/metabolism , Female , High-Throughput Nucleotide Sequencing , Human Umbilical Vein Endothelial Cells , Humans , In Vitro Techniques , Male , Middle Aged , Migraine Disorders/blood , Migraine Disorders/genetics , Migraine Disorders/physiopathology , Reproducibility of Results , Sequence Analysis, RNA , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Vasomotor System/physiopathology
18.
Sci Rep ; 10(1): 22314, 2020 12 18.
Article En | MEDLINE | ID: mdl-33339902

Prevalence of major depression in people with chronic heart failure is higher than in normal populations. Depression in heart failure has become a major issue. Psilocybin-containing mushrooms commonly known as magic mushrooms, have been used since ancient times for their mind healing properties. Their safety in cardiovascular disease conditions is not fully known and may pose as a risk for users suffering from these illnesses. Study investigates the effects and safety of Psilocybe cubensis and Panaeolus cyanescens magic mushrooms use from genus Psilocybe and Panaeolus respectively, in a pathological hypertrophy conditions in which endothelin-1 disorder is a contributor to pathogenesis. We examined the effects of the mushrooms extracts on endothelin-1-induced hypertrophy and tumor necrosis factor-α (TNF- α)-induced cell injury in H9C2 cardiomyocytes. Mushrooms were oven dried and extracted with cold and boiling-hot water. H9C2 cardiomyocytes were induced with endothelin-1 prior to treatment with extracts over 48 h. Cell injury was stimulated with TNF-α. Results proposed that the water extracts of Panaeolus cyanescens and Psilocybe cubensis did not aggravate the pathological hypertrophy induced by endothelin-1 and also protected against the TNF-α-induced injury and cell death in concentrations used. Results support medicinal safe use of mushrooms under controlled conditions and cautioned use of higher concentrations.


Agaricales/chemistry , Endothelin-1/genetics , Hypertrophy/drug therapy , Psilocybe/chemistry , Receptor, Endothelin A/genetics , Animals , Endothelin A Receptor Antagonists/pharmacology , Hallucinogens/chemistry , Hallucinogens/pharmacology , Heart Failure/drug therapy , Heart Failure/genetics , Heart Failure/pathology , Humans , Hypertrophy/chemically induced , Hypertrophy/pathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Phenylpropionates/pharmacology , Psilocybin/chemistry , Psilocybin/pharmacology , Pyridazines/pharmacology , Rats , Receptor, Endothelin A/drug effects , Tumor Necrosis Factor-alpha/genetics
19.
Eur Rev Med Pharmacol Sci ; 24(22): 11776-11782, 2020 11.
Article En | MEDLINE | ID: mdl-33275248

OBJECTIVE: The aim of this study was to investigate the correlations of endothelin-1 (ET-1) gene polymorphisms with the occurrence of hypertensive intracerebral hemorrhage (HICH). PATIENTS AND METHODS: In this case-control study, 100 HICH patients and 100 controls with matched race, age and gender were enrolled as research subjects. Single nucleotide polymorphisms (rs1920453, rs1022436 and rs1035627) in the promoter region of ET-1 gene were typed via conformational difference gel electrophoresis. Whether the distribution frequency of ET-1 genotypes conformed to Hardy-Weinberg equilibrium was evaluated by chi-square test. The correlations of different gene polymorphisms and alleles in the promoter region of ET-1 gene with the occurrence of HICH were analyzed. Furthermore, the associations of rs1920453 polymorphism in the promoter region of ET-1 gene with neurological deficit scores and laboratory parameters of HICH patients were explored. RESULTS: It was found that ET-1 gene polymorphisms (rs1920453, rs1022436 and rs1035627) conformed to Hardy-Weinberg equilibrium (p>0.05). Gene-based association analysis indicated that only rs1920453 polymorphism and alleles were correlated with the occurrence of HICH (p<0.05). However, rs1022436 and rs1035627 polymorphisms and alleles had no association with HICH (p>0.05). Additionally, NIHSS score and high-density lipoprotein cholesterol level were prominently higher in HICH patients with CG and GG genotypes of ET-1 gene polymorphism rs1920453 than those in patients with CC genotype (p<0.05). CONCLUSIONS: Rs1920453 in the promoter region of ET-1 gene is correlated with the occurrence of HICH.


Endothelin-1/genetics , Intracranial Hemorrhage, Hypertensive/genetics , Polymorphism, Single Nucleotide/genetics , Female , Humans , Male , Middle Aged
20.
Int J Mol Sci ; 21(21)2020 Nov 01.
Article En | MEDLINE | ID: mdl-33139635

SGLT2 inhibitors (SGLT2i) slow the progression of chronic kidney disease; however, evidence for the underlying molecular mechanisms is scarce. We investigated SGLT2i-mediated effects on differential gene expression in two independent human proximal tubular cell (HPTC) lines (HK-2 and RPTEC/TERT1) at the mRNA and protein levels under normoglycemic conditions, utilizing IL-1ß as a pro-inflammatory mediator. Microarray hybridization identified 259 genes that were uniformly upregulated by IL-1ß (10 mg/mL) and downregulated by empagliflozin (Empa) (500 nM) after 24 h of stimulation in two independent HPTC lines (n = 2, each). The functional annotation of these genes identified eight pathway clusters. Among 12 genes annotated to the highest ranked cluster (enrichment score, 3.51), monocyte chemoattractant protein-1/CC-chemokine ligand 2 (MCP-1/CCL2) and endothelin-1 (ET-1) were selected for verification at mRNA and protein levels based on their established involvement in the early pathogenesis of chronic kidney disease: IL-1ß upregulated basal MCP-1/CCL2 (15- and 19-fold) and ET-1 (3- and 8-fold) mRNA expression, while Empa downregulated basal MCP-1/CCL2 (0.6- and 0.5-fold) and ET-1 (0.3- and 0.2-fold) mRNA expression as early as 1 h after stimulation and for at least 24 h in HK-2 and RPTEC/TERT1 cells, respectively. The co-administration of Empa inhibited IL-1ß-mediated MCP-1/CCL2 (0.2-fold, each) and ET-1 (0.2-fold, each) mRNA expression as early as 1 h after ligand stimulation and for at least 24 h in both HPTC lines, respectively. This inhibitory effect of Empa on basal and IL-1ß-mediated MCP-1/CCL2 and ET-1 mRNA expression was corroborated at the protein level. Our study presents novel evidence for the interference of SGLT2 inhibition with tubular inflammatory response mechanisms under normoglycemic conditions that might account for SGLT2i-mediated nephroprotection.


Benzhydryl Compounds/pharmacology , Chemokine CCL2/genetics , Endothelin-1/genetics , Gene Expression/drug effects , Glucosides/pharmacology , Interleukin-1beta/pharmacology , Kidney Tubules, Proximal/drug effects , Cell Line , Chemokine CCL2/metabolism , Endothelin-1/metabolism , Gene Expression Profiling/methods , Humans , Kidney Tubules, Proximal/cytology , Kidney Tubules, Proximal/metabolism , Oligonucleotide Array Sequence Analysis/methods
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