Background/Purpose: To investigate alterations in the serum proteome of patients with systemic sclerosis (SSc)-associated pulmonary hypertension (PAH), to identify proteins that correlated with hemodynamic severity and to determine their possible role in the pathogenesis of the disease.

Methods: Eligible patients were recruited from Boston, Lille, Kremlin-Bicêtre and Grenoble SSc and PH referral centers. Patients were included if they fulfilled the following criteria: diagnosis of SSc according to 2013 ACR/EULAR criteria, limited cutaneous subtype, no extensive interstitial lung disease (ILD) according to Goh criteria, and no treatment with PAH-specific therapy. Patients were classified as cases if they had a definitive diagnosis of PAH confirmed by right heart catheterization (RHC) and a serum sample collected on the same day as RHC. They were classified as controls if they had no sign suggestive of PAH on echocardiography.

Results: In a first exploratory step, serum expression of 1129 proteins was assessed in 15 cases and 16 controls by a high-throughput proteomic assay (SOMAscan). We identified 53 proteins differentially expressed between the 2 groups. Among these 53 candidates, only 2 correlated significantly with pulmonary vascular resistance (PVR): chemerin (p=0.01, ρ=0.62) and SET nuclear proto-oncogen (SET) (p=0.01, ρ=0.62).

To validate these results, serum levels of chemerin and SET were measured by ELISA assay in 25 additional cases and 19 additional controls. Chemerin levels were confirmed to be significantly higher in cases (p=0.01) and correlated with PVR (p=0.01, ρ=0.46) in this independent cohort.

In a second step, to study the potential pathophysiological role of chemerin, we performed confocal immunofluorescence analyses on explanted lungs of healthy controls, SSc-ILD without PAH and SSc-PAH patients. Chemerin receptor, CMKLR1, was significantly increased on SSc-ILD and SSc-PAH pulmonary artery smooth muscle cells (PA-SMC).

We then tested the effect of chemerin on PA-SMC proliferation by stimulating PA-SMCs from idiopathic pulmonary arterial hypertension (iPAH) patients with serum from SSc patients with and without PH, in the presence or absence of a CMKLR1 inhibitor. PA-SMCs from iPAH were confirmed to have higher mRNA expression of CMKLR1 than controls (p=0.03). Serum from SSc-PH patients induced a significantly higher PA-SMC proliferation (p=0.005) than serum from controls. This difference was no longer significant (p=0.69) when adding the CMKLR1 inhibitor aNETA.

Conclusion: Chemerin is a surrogate biomarker for PVR in SSc-PAH. Increased chemerin and its receptor, CMKLR1, contribute to the SSc-PAH pathogenesis by inducing PA-SMC proliferation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/biomarkers-of-hemodynamic-severity-of-systemic-sclerosis-associated-pulmonary-arterial-hypertension-by-serum-proteome-analysis/