135. Relevance of the angiotensin II system in temporal artery biopsies from patients with giant-cell arteritis
Creators: name: Alba1, Marco A
name: Planas-Rigol1, Ester
name: Corbera-Bellalta1, Marc
name: Alba-Rovira1, Roser
name: Kamberovic1, Farah
name: Prieto-Gonzalez1, Sergio
name: Garcia-Martinez2, Ana
name: Hernandez-Rodriguez1, Jose
name: Espigol-Frigole1, Georgina
name: Grau3, Josep M
name: Cid1, Maria C
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Retrospective studies have shown that treatment with angiotensin II receptor 1 (ATR1) blockers (ARB) was associated with lower relapse rate and glucocorticoid (GC)-sparing effect in patients with giant cell arteritis (GCA) (1,2). In this study, we investigate the expression and functional activity of the angiotensin II (ATII) system in temporal arteries (TA) from patients with GCA. <strong>Methods:</strong> 40 GCA TA and 18 control arteries were analyzed. Expression of angiotensinogen (AGT), angiotensin-converting enzyme (ACE), ACE2, and ATR1 was investigated by quantitative real-time PCR in TA. Distribution of ATII system was qualitatively assessed by confocal microscopy. Effect of ATII and ATR1-blockade on selected cytokines was investigated in a co-culture system of PBMC and TA-derived VSMC. Modulation of the ATII system by GC was addressed using an <em>ex vivo</em> model of cultured TA. Multiplex Luminex system was used to quantify the concentration of 30 cytokines with inflammatory, Th1/Th2, chemokine, or growth factor activity in supernatants of cultured GCA TA incubated with ATII or ARB losartan. <strong>Results:</strong> ACE and ACE2 mRNA transcripts were overexpressed and downregulated in GCA TA, respectively. By confocal microscopy, ATII, ACE, and ATR1 expression was qualitatively higher in GCA lesions (Figure 1A). The local ATII system identified in GCA lesions required multi-cellular cooperation as VSMC mainly expressed ATII and ATR1 while PBMC predominantly expressed ACE. <em>In vitro</em>, ATII increased mRNA expression of IL-1β, IL-6, CCL-2, ICAM-1, and VCAM in VSMC co-cultured with PBMC and of IL-1β, IL-6, TNF-α, CCL-2, ICAM-1, and VCAM-1 in PBMC. Losartan reversed these changes and reduced basal expression of IFN-γ, CCL-2, ICAM-1, and VCAM-1 in PBMC. In cultured GCA TA, dexamethasone reduced ACE gene expression and increased ATR1 and ACE2 transcripts (Figure 1B). Cytokine determination in supernatants of cultured GCA TA after incubation with ATII or losartan showed that ATII increased IL-6, VEGF, G-CSF, IL-15, CCL2, and CXCL9 concentration whereas losartan tended to augment anti-inflammatory IL-10, the latter also confirmed at mRNA level by RT-PCR (Figure 1C). <strong>Conclusions.</strong> Our findings suggest that the ATII system may play a role in vascular inflammatory lesions of GCA and that observed anti-inflammatory effects of ARB in GCA may be mediated in part by increase of IL-10. <strong>Disclosures: </strong>Marco A Alba was supported by the Biomedicine International Training Research program for Excellent Clinician-Scientists (BITRECS), IDIBAPS. Sergio Prieto-González reports lecturing for Roche; meeting attendance support from Italfarmo and CSL Behring José Hernández-Rodríguez reports consulting for Sobi; lecturing for Novartis; meeting attendance support from Sobi and Novartis. Georgina Espigol-Frigolé reports consulting for Janssen and Hoffmann-La Roche; meeting attendance suport from Boehringer Ingelheim. María C Cid reports a research grant from Kiniksa; consulting for Janssen, GSK, and Abbvie; educational from GSK and Vifor; meeting attendance support from Roche and Kiniksa. Supported by Ministerio Ciencia e Innovación /AEI/10.13039/501100011033 (Project PID2020-114909RB-I00). Ester Planas-Rigol , Marc Corbera-Bellalta, Roser Alba-Rovira, Farah Kamberovic, Ana García-Martínez, Josep M. Grau. No financial disclosures to be reported. <strong>Figure 1.</strong> A) Expression of ATII system in TA sections from a control and a patient with GCA. B) Changes in mRNA concentration of AGT, ACE, ACE2, ACE/ACE2 ratio, and ATR1 induced by dexamethasone in cultured GCA TA. C) Quantification (left) of IL-10 in supernatant fluid of 5 cultured TA from patients with GCA incubated with ATII or losartan. Gene expression (right) of IL-10 in cultured GCA TA determined by RT-PCR.