Background/Purpose: Giant cell arteritis (GCA) is a large and medium size-vessel granulomatous vasculitis that predominantly affects the aorta and its major branches. The renin-angiotensin-aldosterone system (RAAS) is a multiple-step cascade of vasoactive peptides that plays a major role in the regulation of blood pressure and electrolyte balance. Angiotensin II (ATII), the major effector molecule of the RAAS, has emerged as a powerful pro-inflammatory peptide and pharmacological blockade of this system results in anti-inflammatory effects. In this line, a previous observational study suggested that treatment with angiotensin II blockers (ARB) was associated with lower relapse rate and glucocorticoid (GC)-sparing effect in patients with GCA (Alba MA, Semin Arthritis Rheum. 2014). Our objective was to investigate the expression and functional activity of the ATII system in GCA temporal arteries (TA).

Methods: 40 involved TA from patients with GCA and 18 normal arteries from controls were included. Angiotensinogen (AGT), angiotensin-converting enzyme (ACE), ATII receptor 1 (ATR1), and counter-regulatory ACE2 expression was investigated by quantitative real-time PCR in TA. Distribution of ATII system components was assessed by confocal microscopy. The effect of ATII and ATR1-blockade on pro-inflammatory cytokine production was investigated in a co-culture system of peripheral blood mononuclear cells (PBMC) and TA-derived vascular smooth muscle cells (VSMC). In addition, modulation of the ATII system by GC was addressed using an ex vivo model of cultured TA.

Results: A local ATII system, mainly characterized by constitutive expression of ATG, overexpression ACE mRNA transcripts and a down-regulation of ACE2 was identified in GCA inflamed arteries (figure 1). By confocal microscopy, ATII, ACE, and ATR1 expression was identified to be qualitatively higher in GCA sections in comparison with a control TA. The local ATII system appears to require multi-cellular cooperation as VSMC were the main cells expressing ATII and ATR1 while ACE was predominantly expressed by inflammatory infiltrating cells. In vitro, ATII was able to induce a pro-inflammatory phenotype in PBMC and co-cultured VSMC: IL-1β, IL-6, TNF-α, CCL-2, ICAM-1, and VCAM-1 mRNA expression measured by real-time quantitative PCR was increased in PBMC whereas IL-1β, IL-6, CCL-2, ICAM-1, and VCAM transcripts increased in VSMC co-cultured with PBMC. Losartan, an ARB, was able to reverse these changes and interestingly, it reduced basal expression of IFN-γ, CCL-2, ICAM-1, and VCAM-1 in PBMC. Finally, we observed that dexamethasone was able to modulate the expression of the ATII system by reducing ACE gene expression and increasing ATR1 and ACE2 in an ex-vivo model of cultured temporal arteries.

Conclusion: Our findings suggest that the ATII system may play a role in vascular inflammatory lesions of GCA. Thus, interference of the RAAS system may be a potential adjunctive therapeutic option for patients with GCA.

MA Alba and E Planas-Rigol contributed equally to this study. Supported by Ministerio de Economía y Competitividad (SAF 2017/88275-R). MA Alba was supported by BITRECS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/expression-and-functional-activity-of-the-angiotensin-ii-system-in-temporal-artery-lesions-from-patients-with-giant-cell-arteritis/