title: Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Systemic Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Lozano
authors.forename: M
authors.initials: M
authors.lastname: Segarra
authors.forename: M
authors.initials: M
authors.lastname: Corbera-Bellalta
authors.forename: A
authors.initials: A
authors.lastname: García-Martínez
authors.forename: G
authors.initials: G
authors.lastname: Espígol-Frigolé
authors.forename: A
authors.initials: A
authors.lastname: Plà-Campo
authors.forename: J
authors.initials: J
authors.lastname: Hernández-Rodríguez
authors.forename: M C
authors.initials: MC
authors.lastname: Cid
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D002545:Brain Ischemia / Q000097:blood / Q000209:etiology / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D019332:Endothelin-1 / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D000072396:Endothelin-Converting Enzymes; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D013700:Giant Cell Arteritis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D018917:Optic Neuropathy, Ischemic / Q000097:blood* / Q000209:etiology / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013699:Temporal Arteries / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D005938:Glucocorticoids; D053583:Interleukin-1beta; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D017466:Receptors, Endothelin; C095477:platelet-derived growth factor AB; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes