endothelin-1 and Giant-Cell-Arteritis

Giant-cell arteritis (GCA) is an inflammatory disease of large/medium-sized arteries, frequently involving the temporal arteries (TA). Inflammation-induced vascular remodelling leads to vaso-occlusive events. Circulating endothelin-1 (ET-1) is increased in patients with GCA with ischaemic complications suggesting a role for ET-1 in vascular occlusion beyond its vasoactive function.. To investigate whether ET-1 induces a migratory myofibroblastic phenotype in human TA-derived vascular smooth muscle cells (VSMC) leading to intimal hyperplasia and vascular occlusion in GCA.. Immunofluorescence/confocal microscopy showed increased ET-1 expression in GCA lesions compared with control arteries. In inflamed arteries, ET-1 was predominantly expressed by infiltrating mononuclear cells whereas ET receptors, particularly ET-1 receptor B (ET. ET-1 is upregulated in GCA lesions and, by promoting VSMC migration towards the intimal layer, may contribute to intimal hyperplasia and vascular occlusion in GCA.

Topics: Actins; Aged; Blotting, Western; Case-Control Studies; Cell Movement; Endothelin Receptor Antagonists; Endothelin-1; Female; Fluorescent Antibody Technique; Focal Adhesion Kinase 1; Giant Cell Arteritis; Humans; Hyperplasia; In Vitro Techniques; Leukocytes, Mononuclear; Male; Microscopy, Confocal; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; src-Family Kinases; Tunica Intima; Vascular Remodeling

Approximately 15-20% of patients with giant-cell arteritis (GCA) develop ischaemic complications often preceded by transient ischaemia. The expression of the endothelin (ET) system in GCA lesions was investigated to assess its relationship with the development of ischaemic complications.. Plasma ET-1 was quantified by immunoassay in 61 patients with biopsy-confirmed GCA and 16 healthy donors. ET-1, endothelin-converting enzyme (ECE-1) and endothelin receptor (ET(A)R and ET(B)R) messenger RNA were measured by real-time quantitative reverse transcriptase-PCR in temporal arteries from 35 of these patients and 19 control arteries. Proteins were measured by immunoassay and Western blot.. ET-1 concentration was increased at the protein level in temporal artery samples from GCA patients compared with controls (0.98 (SEM 0.32) vs 0.28 (SEM 0.098) fmol/mg, p = 0.028). ECE-1, ET(A)R and ET(B)R/actin ratios (Western blot) were also significantly higher in GCA patients. Intriguingly, mRNA expression of ET-1, ECE-1 and both receptors was significantly reduced in GCA lesions compared with control arteries. When investigating mechanisms underlying these results, platelet-derived growth factor and IL-1beta, present in GCA lesions, were found to downregulate ET-1 mRNA in cultured human temporal artery-derived smooth muscle cells. Glucocorticoid treatment for 8 days did not result in significantly decreased endothelin tissue concentration (0.87 (SEM 0.2) vs 0.52 (SEM 0.08); p = 0.6). Plasma endothelin concentrations were higher in patients with ischaemic complications (1.049 (SEM 0.48) vs 1.205 (SEM 0.63) pg/ml, p = 0.032).. The endothelin system is increased at the protein level in GCA lesions creating a microenvironment prone to the development of ischaemic complications. Recovery induced by glucocorticoids is delayed, indicating persistent exposure to endothelin during initial treatment.

Topics: Aged; Aged, 80 and over; Aspartic Acid Endopeptidases; Brain Ischemia; Cells, Cultured; Down-Regulation; Endothelin-1; Endothelin-Converting Enzymes; Female; Gene Expression Regulation; Giant Cell Arteritis; Glucocorticoids; Humans; Interleukin-1beta; Male; Metalloendopeptidases; Middle Aged; Muscle, Smooth, Vascular; Optic Neuropathy, Ischemic; Platelet-Derived Growth Factor; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Temporal Arteries

Endothelin (ET)-1 has been implicated in the atherosclerotic process and during inflammation. Similarity in the development process of giant cell arteritis (GCA) and atherosclerosis exists. Several ET receptor antagonists have been developed, principally to target cardiovascular disease states. High doses of corticosteroids currently are used in the treatment of GCA, whereas other treatments are not as reliably effective. The present study was performed to elucidate the role for ET-1, ET(A), and ET(B) receptors in GCA.. Experimental, retrospective immunohistochemical study of temporal arteries using archival formalin-fixed, paraffin-embedded tissue.. The study included 10 patients with GCA and 10 control patients with clinically suspected GCA but diagnosed not to have GCA.. Immunohistochemistry, with anti ET-1, anti-ET(A), and anti-ET(B) antibodies, was performed on formalin-fixed and paraffin-embedded temporal arteries.. Endothelin-1, ET(A), and ET(B) receptor immunostaining intensities were quantified.. Temporal arteries from the patients with GCA showed the typical histologic features, including intimal thickening, disruption or loss of the elastic lamina, and inflammatory infiltrates of lymphocytes, macrophages, and multinucleated giant cells. These features were associated with increased ET-1 and ET(B) receptor immunoreactivity in the medial layer of the temporal arteries and endothelial cells in patients with GCA compared with the controls. The increased ET-1 and ET(B) receptor immunoreactivity occurred in vascular smooth muscle cells (SMCs) and multinucleated giant cells. The ET-1 and ET(B) receptor immunoreactivity correlated with the degree of systemic inflammation. No changes were observed in ET(A) receptor expression in SMCs or endothelial cells compared with controls.. The results suggest a role for ET-1 and ET(B) receptors in GCA. Inhibiting the ET system may provide a corticosteroid-sparing alternative in the treatment of GCA.

Topics: Aged; Aged, 80 and over; C-Reactive Protein; Endothelin-1; Female; Giant Cell Arteritis; Humans; Immunoenzyme Techniques; Male; Middle Aged; Muscle, Smooth, Vascular; Receptor, Endothelin A; Receptor, Endothelin B; Temporal Arteries

To test the hypothesis that endothelin-1 is increased in giant cell arteritis.. Interventional case series. The medical history of four patients who presented to the University Eye Clinic Basel, Switzerland, with giant cell arteritis is reported. Endothelin-1 plasma levels were measured in all patients. The relevant medical literature was reviewed.. All patients presented with typical histopathological signs of giant cell arteritis in the temporal artery biopsy. The erythrocyte sedimentation rate was increased in two patients. All patients showed significantly increased endothelin-1 plasma levels, ranging between 3.13 to 4.82 pg/ml (reference value for females: 1.42 pg/ml +/- 0.28 standard deviation, for males: 1.67 pg/ml +/- 0.34 standard deviation).. The data obtained from the patients so far examined indicate that the level of circulating endothelin-1 is increased in giant cell arteritis. The clinical relevance of such an increase needs to be further evaluated.

Topics: Aged; Aged, 80 and over; Biopsy; Endothelin-1; Female; Giant Cell Arteritis; Humans; Male; Temporal Arteries