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- Title
Autoantibodies Targeting AT 1 - and ET A -Receptors Link Endothelial Proliferation and Coagulation via Ets-1 Transcription Factor.
- Authors
Catar, Rusan; Herse-Naether, Melanie; Zhu, Nan; Wagner, Philine; Wischnewski, Oskar; Kusch, Angelika; Kamhieh-Milz, Julian; Eisenreich, Andreas; Rauch, Ursula; Hegner, Björn; Heidecke, Harald; Kill, Angela; Riemekasten, Gabriela; Kleinau, Gunnar; Scheerer, Patrick; Dragun, Duska; Philippe, Aurelie
- Abstract
Scleroderma renal crisis (SRC) is an acute life-threatening manifestation of systemic sclerosis (SSc) caused by obliterative vasculopathy and thrombotic microangiopathy. Evidence suggests a pathogenic role of immunoglobulin G (IgG) targeting G-protein coupled receptors (GPCR). We therefore dissected SRC-associated vascular obliteration and investigated the specific effects of patient-derived IgG directed against angiotensin II type 1 (AT1R) and endothelin-1 type A receptors (ETAR) on downstream signaling events and endothelial cell proliferation. SRC-IgG triggered endothelial cell proliferation via activation of the mitogen-activated protein kinase (MAPK) pathway and subsequent activation of the E26 transformation-specific-1 transcription factor (Ets-1). Either AT1R or ETAR receptor inhibitors/shRNA abrogated endothelial proliferation, confirming receptor activation and Ets-1 signaling involvement. Binding of Ets-1 to the tissue factor (TF) promoter exclusively induced TF. In addition, TF inhibition prevented endothelial cell proliferation. Thus, our data revealed a thus far unknown link between SRC-IgG-induced intracellular signaling, endothelial cell proliferation and active coagulation in the context of obliterative vasculopathy and SRC. Patients' autoantibodies and their molecular effectors represent new therapeutic targets to address severe vascular complications in SSc.
- Subjects
TRANSCRIPTION factors; MITOGEN-activated protein kinases; G protein coupled receptors; BLOOD coagulation; PREPROENDOTHELIN; FC receptors; AUTOANTIBODIES; BOTULINUM A toxins
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 1, p244
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms23010244