endothelin-1 and Calcinosis

End-stage renal disease patients receiving chronic haemodialysis via arteriovenous access often develop various cardiovascular complications, including vascular calcification, cardiac-vascular calcification and atherosclerotic coronary disease. This review describes recently published studies that demonstrate a high incidence of pulmonary hypertension among patients with end-stage renal disease receiving long-term haemodialysis via a surgical arteriovenous fistula. Both end-stage renal disease and long-term haemodialysis via arteriovenous fistula may be involved in the pathogenesis of pulmonary hypertension by affecting pulmonary vascular resistance and cardiac output.. Morbidity and mortality from cardiovascular disease are greatly increased in patients on maintenance haemodialysis therapy. Using Doppler echocardiography, we found a significant increase in cardiac output in 40% of chronic haemodialysis patients, probably related to the large arteriovenous access or altered vascular resistance as a result of the local vascular tone and function expressed by the imbalance between vasodilators such as nitric oxide, and vasoconstrictors such as endothelin-1.. We propose different potential mechanisms as explanations for the development of pulmonary hypertension. Hormonal and metabolic derangement associated with end-stage renal disease might lead to pulmonary arterial vasoconstriction and an increase in pulmonary vascular resistance. Pulmonary arterial pressure may be further increased by high cardiac output resulting from the arteriole-venous access itself, worsened by commonly occurring anaemia and fluid overload.

Topics: Adult; Aged; Blood Pressure; Calcinosis; Cardiac Output; Echocardiography, Doppler; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Pulmonary Artery; Renal Dialysis; Time Factors; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

Cardiac valve calcification (CVC) and left ventricular (LV) alterations are frequent complication in end-stage renal disease (ESRD). We determined the prevalence of CVC and LV hypertrophy (LVH) in ESRD patients before renal replacement therapy and 12 months after peritoneal dialysis (PD).. A prospective longitudinal of 50 incident PD patients was studied. Demographic and clinical data were recorded and blood assayed at baseline and after 1-year of follow-up. CVC and LVH were evaluated by M-mode two-dimensional echocardiography.. CVC of the mitral and aortic valves and of both valves were noted in 30, 18 and 10% of patients, respectively. After 12 months of PD regimen, 20% patients had aortic, 24% mitral and 8% had calcification of both valves. After one year of PD, LVH was 62 and 36% in patients with and without CVC, respectively (p < 0.05). Endothelin-1 is an independent predictor of CVC at the baseline, while nitric oxide is inversely an independent predictor at the end of follow-up.. CVC is associated with LVH in PD patients. These findings identified a potential role for monitored markers to be incorporated into therapeutic strategies aimed at detection and treatment of cardiovascular complications and prevention strategies.

Topics: Adult; Aged; Aorta; Biomarkers; Calcinosis; Echocardiography; Endothelin-1; Female; Heart Valve Diseases; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Mitral Valve; Peritoneal Dialysis; Prospective Studies; Young Adult

The coronary artery calcification (CAC) is clinically considered as one of the important predictors of atherosclerosis. Several studies have confirmed that endothelin-1(ET-1) plays an important role in the process of atherosclerosis formation. The aim of this study was to investigate whether big ET-1 is associated with CAC.. A total of 510 consecutively admitted patients from February 2011 to May 2012 in Fu Wai Hospital were analyzed. All patients had received coronary computed tomography angiography and then divided into two groups based on the results of coronary artery calcium score (CACS). The clinical characteristics including traditional and calcification-related risk factors were collected and plasma big ET-1 level was measured by ELISA. Patients with CAC had significantly elevated big ET-1 level compared with those without CAC (0.5 ± 0.4 vs. 0.2 ± 0.2, P<0.001). In the multivariate analysis, big ET-1 (Tertile 2, HR = 3.09, 95% CI 1.66-5.74, P <0.001, Tertile3 HR = 10.42, 95% CI 3.62-29.99, P<0.001) appeared as an independent predictive factor of the presence of CAC. There was a positive correlation of the big ET-1 level with CACS (r = 0.567, p<0.001). The 10-year Framingham risk (%) was higher in the group with CACS>0 and the highest tertile of big ET-1 (P<0.01). The area under the receiver operating characteristic curve for the big ET-1 level in predicting CAC was 0.83 (95% CI 0.79-0.87, p<0.001), with a sensitivity of 70.6% and specificity of 87.7%.. The data firstly demonstrated that the plasma big ET-1 level was a valuable independent predictor for CAC in our study.

Topics: Adult; Aged; Calcinosis; Calcium; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Female; Humans; Male; Middle Aged; Multivariate Analysis

Nephrogenic systemic fibrosis (NSF) is characterized by systemic fibrosis and abnormal calcification in patients with severe renal dysfunction. It is considered that gadolinium (Gd)-containing contrast agents used for magnetic resonance imaging trigger the development of NSF. However, the causative role of Gd and the mechanism of Gd-induced fibrosis and calcification in NSF are unknown. Recently, it has been known that endothelin-1 (ET-1)/ET receptor (ETR) signalling regulates fibrosis and calcification. The objective was to elucidate the role of ET-1/ETR signalling in Gd-induced fibrosis and calcification in NSF. First, we demonstrated that Gd enhanced proliferation and calcification of human adipose tissue-derived mesenchymal stem cells (hMSC) in vitro. Next, we examined the expression of ET-1 and ETR-A in hMSC using proliferation or calcification assay. ET-1 and ETR-A expression in hMSC treated with Gd were elevated. ET-1/ETR signalling inhibitor, bosentan, inhibited Gd-induced proliferation and calcification of hMSC. In addition, bosentan inhibited Gd-induced phosphorylation of ERK and Akt in hMSC. Plasma ET-1 levels of the patients were significantly higher than these of normal individuals and systemic sclerosis patients. In immunofluorescence staining, the expression of ETR-A in fibroblasts in dermal fibrosis lesion of NSF was increased. We conclude that Gd induces proliferation and calcification of hMSC via enhancement of ET-1/ETR signalling. Our results contribute to understand the pathogenesis of NSF.

Topics: Adolescent; Bosentan; Calcinosis; Cell Proliferation; Cells, Cultured; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Gadolinium; Humans; Magnetic Resonance Imaging; Male; Mesenchymal Stem Cells; Middle Aged; Nephrogenic Fibrosing Dermopathy; Receptor, Endothelin A; Signal Transduction; Sulfonamides

Aortic valve stenosis (AS) is an actively regulated pathobiological process which has an inflammation origin, and manifests as an accumulation of lipids and, ultimately, calcification of the aortic valve tissue. Increased plasma levels of the proinflammatory factor endothelin-1 (ET-1) have been reported in AS. Moreover, increased tissue levels of ET-1 and its ET(A) receptor, which mediates the fibrotic and proliferative effects of ET-1, have been reported in stenotic aortic valves. The study aim was to determine whether endothelin receptor antagonism has an effect on the supposed receptor-mediated uptake of ET-1 to aortic valves when ET-1 may be involved in the pathogenesis of AS.. By using valve tissue explants in culture, it was determined whether the ET(A)-ET(B) receptor antagonist tezosentan was capable of reducing the uptake of 125I-labeled ET-1 to human aortic valves. Aortic valves were obtained from 16 patients (11 males, five females; mean age 71 +/- 11.2 years) and from two donors without AS (as controls) at the time of aortic valve or aortic root surgery. Valve tissue samples were cultured in ET-1 (10 nmol/l), in the presence or absence of tezosentan (10 nmol/l).. ET-1 uptake was found to be pronounced in the calcified areas of the valve, and tezosentan markedly reduced the receptor-mediated uptake of 125I-labeled ET-1. The inhibitory effect was most evident in the well-calcified part of the valve. The gene expression levels of the ET receptors ET(A) and ET(B) were unaltered in human aortic valves during a four-day exposure to the antagonist.. The ability of the ET(A)-ET(B) receptor antagonist tezosentan to inhibit ET-1 uptake in valve tissue suggests that continuous ET antagonist therapy might serve as new strategy to slow down the pathophysiological processes of AS.

Topics: Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Cells, Cultured; Drug Repositioning; Endothelin A Receptor Antagonists; Endothelin-1; Female; Humans; Inflammation; Lipid Metabolism; Male; Middle Aged; Pyridines; Receptor, Endothelin A; Tetrazoles; Vasodilator Agents

Epidemiological studies have reported an association between arterial calcification and bone loss after menopause. However, the underlying mechanism of the association remains unclear. Therefore, to explore the possible mechanisms of the association, we tried to develop a new combined model rat of ovariectomy (OVX, an animal model of osteoporosis) and vitamin D(3) plus nicotine (VDN rat, an animal model of arterial calcification). We tested them by using sham-operated control rats (SC), OVX control rats (OC), and OVX plus VDN-treated rats (OVN). Dissections were performed twice at 4 (4SC, 4OC, and 4OVN) and 8 (8SC, 8OC, and 8OVN) weeks after treatment. 8OVN showed bone loss and arterial calcification, although 8OC showed only bone loss. Moreover, arterial calcium content was associated with indexes of bone loss at 8 weeks. Thus, the OVN rat is considered a good model to examine the relationship of the two disorders after menopause. Additionally, the arterial endothelin-1 (ET-1, a potent regulator of arterial calcification) levels increased in both 4OVN and 8OVN, and the level was associated with arterial calcium content at 8 weeks. Furthermore, the arterial endothelial nitric oxide synthase (eNOS) protein, which is an enzyme that produces nitric oxide (an antiatherosclerotic substance), was significantly reduced in only 8OVN. Estrogens affect the alterations of the eNOS and ET-1 proteins. Therefore, we suggest that impairment of the ET-1- and NO-producing system in arterial tissue during periods of rapid bone loss by estrogen deficiency might be a mechanism of the relationship between the two disorders seen in postmenopausal women.

Topics: Animals; Arteries; Calcinosis; Calcium; Cholecalciferol; Disease Models, Animal; Endothelin-1; Estradiol; Female; Femur; Nicotine; Nitric Oxide Synthase Type III; Osteoporosis; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Tibia

Loss of oestrogen synthesis capacity after menopause contributes to increases in arterial stiffness and calcification. Exercise training improves arterial stiffness and calcification. However, the mechanism of exercise training-induced improvement of arterial stiffness and calcification remains unclear.. We examined the mechanism by using aortas of sham-operated rats (sham control; SC), ovariectomized rats (OVX control; OC), OVX plus treatment with vitamin D(3) plus nicotine (VDN) rats (OV sedentary; OVSe), which is an animal model of endothelial dysfunction and arterial calcification, and voluntary running wheel exercise for 8 weeks plus OVX plus VDN rats (OV exercise; OVEx).. The arterial tissue calcium and endothelin-1 (ET-1: a vasoconstrictor peptide and a potent regulator of arterial calcification) levels were significantly higher in OVSe rats compared with the SC and OC rats, whereas these levels in the OVEx rats were significantly lower than in the OVSe rats. Additionally, arterial expression of endothelial nitric oxide synthase (eNOS), which is an enzyme that produces nitric oxide (NO: a vasodilator substance), was reduced in OVSe rats. However, exercise training prevented the decrease in eNOS expression. Moreover, there was a significant positive correlation between arterial calcium level and arterial ET-1 level.. These findings suggest that exercise training-induced improvement of ET-1 and NO prevents the impairment of endothelial function after menopause in females, and this improvement may result in less arterial calcification.

Topics: Animals; Aortic Diseases; Calcinosis; Calcium; Citrate (si)-Synthase; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Estradiol; Female; Motor Activity; Muscle, Skeletal; Nitric Oxide Synthase Type III; Ovariectomy; Postmenopause; Rats; Rats, Sprague-Dawley

Ossification of the posterior longitudinal ligament (OPLL) of the spine is characterized by progressive ectopic bone formation in the spinal ligament. To identify the genes related to ossification affected by mechanical stress during OPLL, analyses using cDNA microarray were carried out using cultured human spinal ligament cells that had been subjected to uniaxial cyclic stretching. Samples were obtained from a total of 14 patients: seven cervical or thoracic OPLL patients and seven control patients. Spinal ligament cells derived from tissues of OPLL (OPLL cells) and control (non-OPLL cells) patients were subjected to uniaxial sinusoidal cyclic stretching (0.5 Hz, 20% stretch) for various time periods (0-9 hours). cDNA microarrays revealed that ranges of distribution of both up- and downregulated genes evoked by cyclic stretching were significantly wider in OPLL cells than in non-OPLL cells. Increases in the mRNA expression of endothelin-1 (ET-1) as well as various marker genes related to ossification were also observed. mRNA expression of ET-1 and alkaline phosphatase was increased by mechanical stress in a time-dependent manner, while addition of ET-1 to static cultures of OPLL cells increased mRNA expression of alkaline phosphatase in a dose-dependent manner. During 9 hours of cyclic stretching, ET-1 release increased to about sixfold the amount observed in nonstretched cells. In non-OPLL cells, neither cyclic stretching nor ET-1 induced any increase in alkaline phosphatase expression. These results suggest that mechanical stress promotes the progression of ossification in OPLL cells through autocrine and/or paracrine mechanisms of ET-1.

Topics: Aged; Alkaline Phosphatase; Calcinosis; Cells, Cultured; Cervical Vertebrae; Endothelin-1; Ethers; Gene Expression; Gene Expression Profiling; Humans; Hydrocarbons, Fluorinated; Longitudinal Ligaments; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Oligopeptides; Ossification of Posterior Longitudinal Ligament; Piperidines; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stress, Mechanical; Thoracic Vertebrae

Mitral annulus calcification (MAC) is a chronic degenerative noninflammatory process. The goal of this study was to determine endothelin-1 (ET-1) and nitric oxide (NOx) levels in patients with MAC and compare them with those in normal subjects. The study group included 39 patients [26 females (66%), age, 63 +/- 8 years] with MAC and 20 [11 females (55%), age, 61 +/- 7 years] healthy subjects. The patients were divided into two subgroups, group A with severe MAC and group B with mild MAC, according to the severity of the MAC. Plasma ET-1 levels were higher and NOx levels were lower in patients than controls [(6.5 +/- 5.6 pg/mL vs 3.7 +/- 2.9 pg/mL for ET-1 and 35.0 +/- 10.6 micromol/L vs 42.3 +/- 9.9 micromol/L for NOx; P < 0.05 for both)]. In the subgroups, ET-1 levels were higher in group A than group B (8.65 +/- 6.84 pg/mL vs 4.74 +/- 3.45 pg/mL, P < 0.05) and the control group (8.65 +/- 6.84 pg/mL vs 3.70 +/- 2.88 pg/mL, P < 0.05). There was no difference between group B and the control group. Plasma NOx levels were significantly decreased in group A compared to controls (32.22 +/- 11.88 micromol/L vs 42.25 +/- 9.99 micromol/L, P < 0.05). However, no significant difference was observed between group B (37.38 +/- 9.06 micromol/L) and the other groups. Diabetes mellitus, coronary artery disease, and dyslipidemia were significantly associated with ET-1 levels. However, this association was not observed for NOx. In conclusion, patients with MAC have increased ET-1 and decreased NOx levels. This seems to be more prominent in patients with severe MAC.

Topics: Aged; Calcinosis; Coronary Disease; Diabetes Mellitus; Echocardiography; Echocardiography, Doppler, Color; Endothelin-1; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Mitral Valve; Nitrates; Nitric Oxide; Nitrites

We have previously shown that an endothelin receptor antagonist can regress medial arterial calcification in a rat model. The aim of this study was to characterize the phenotypic changes of vascular smooth muscle cells during calcification and mineral loss, in order to understand better the underlying mechanisms. Control Wistar rats were compared with rats treated only with warfarin/ vitamin K1 (15 mg/kg per day) for 8 weeks, or in combination with darusentan (30 mg/kg per day) for the final 4 weeks. Vascular smooth muscle cell, bone cell and macrophage phenotypes were evaluated by the local expression of alpha-actin, tartrate-resistant acid phosphatase and ED-1, respectively. Proteins involved in the modulation of bone resorption like osteopontin and osteoprotegerin were also evaluated by immunohistochemistry. The warfarin/vitamin K1 treatment increased medial arterial calcification ninefold (P < 0.05). At sites of calcification, there was a decrease in alpha-actin localization, and an appearance of osteopontin immunostaining. Histochemical and immunostaining for osteoclast and macrophage markers, as well as for osteoprotegerin, were negative. Although the extent of calcification foci was reduced by darusentan, protein localization in the calcified areas was not modified. Thus, the development of medial arterial calcification produces a phenotypic change in vascular smooth muscle cells that does not appear to be normalized in regions remaining calcified during mineral loss.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Calcinosis; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Macrophages; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteoclasts; Osteopontin; Osteoprotegerin; Phenotype; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptors, Endothelin; Vitamin K 1; Warfarin

We observed changes of endothelin content and endothelin mRNA in vivo in vascular calcification and in vitro in calcification of vascular smooth muscle cells to explore the role of endothelin in vascular calcification. Calcification model in vivo was induced by administration of Vitamin D(3) plus nicotine. Calcification of vascular smooth muscle cells (VSMCs) was induced by beta-glycerophosphate. Endothelin content was measured by using radioimmunoassay. Endothelin mRNA amount was determined by using competitive quantitative RT-PCR. The results showed that calcium content, 45Ca(2+) uptake and alkaline phosphatase (ALP) activity were increased in calcified VSMCs, compared with controls, but were decreased, compared with calcified VSMCs plus BQ123 group. The endothelin content in the medium and endothelin mRNA in VSMCs were elevated by 35 and 120% (P<0.05), respectively, compared with those normal VSMCs. Calcium content, 45Ca(2+) accumulation and ALP activity in calcified arteries increased by 5.0-, 1.4-, and 1.4-fold. The endothelin levels in plasma and aorta as well as the amount of endothelin mRNA in calcified aorta were increased by 102, 103, and 22%, respectively, compared with control group. However, calcium content, 45Ca(2+) uptake and ALP activity in VDN plus bosentan group was 33, 36.7, and 40.4% lower than those in VDN group. These results indicated an upregulated endothelin gene expression as well as an increased production of endothelin in calcified aorta and VSMCs with BQ123 and bosentan significantly reducing vascular calcification. This suggested that endothelin might be involved in pathogenesis of vascular calcification.

Topics: Animals; Aorta; Calcinosis; Endothelin-1; Glycerophosphates; In Vitro Techniques; Muscle, Smooth, Vascular; Peptides, Cyclic; Rats; RNA, Messenger; Up-Regulation

The changes in endothelium-derived vascular regulatory factors during dobutamine (DOB)-induced myocardial ischemia (MI) were investigated in 21 patients with Kawasaki disease aged from 11 months to 18 years. They were classified into an ischemia group (8 patients) and a non-ischemia group (13 patients) based on the results of 99mTc myocardial scintigraphy and DOB stress 99mTc myocardial scintigraphy. In the ischemia group, MI was relatively mild, because there were ischemic changes on the electrocardiogram and no significant symptoms during DOB stress. Catheters were positioned near the orifice of the coronary artery (Ao) and at the coronary sinus (CS). Hemodynamics and the blood concentrations of lactic acid and endothelin-1, as well as NO3-, 6-keto-prostaglandin F1alpha, and thromboxane B2, (which are inactive metabolites of nitric oxide, prostaglandin I2 and thromboxane A2, respectively), were measured at rest and after DOB stress (maximum dose: 30 microg x kg(-1) x min(-1)). The CS/Ao ratio was determined for all parameters. The rate-pressure product, an index of work load, and the cardiac index were significantly increased by DOB stress in both groups. Coronary angiography showed no vasospasm of the epicardial coronary arteries before or after DOB stress in either group. The plasma concentrations of endothelin-1 and 6-keto-prostaglandin F1alpha were significantly increased after DOB stress in the ischemia group, but the serum concentration of NO did not increase. The lack of an increase in NO production during DOB stress may have contributed to the worsening of MI in patients with Kawasaki disease.

Topics: Adolescent; Calcinosis; Cardiomyopathies; Child; Child, Preschool; Coronary Angiography; Dobutamine; Endothelin-1; Endothelins; Female; Hemodynamics; Humans; Infant; Lactic Acid; Male; Mucocutaneous Lymph Node Syndrome; Myocardial Ischemia; Nitrates; Nitric Oxide; Prostaglandins F; Rest; Stress, Physiological; Thromboxane B2