Relm Protein-Induced Cxcr3 Ligands in Pulmonary Hypertension

Abstract In pulmonary hypertension (PH), inflammation and angiogenesis go hand in hand. Inflammatory mediators exert direct effects on endothelial (EC) and vascular smooth muscle cells (VSMC) and attract leukocytes to affected vascular beds. Resistin-like molecules (RELM) were previously implicated in vascular remodeling in PH. Structural and functional parallels can be drawn between chemokines and RELMs. Resistin (Retn) stimulates SMC proliferation and regulates EC adhesion and apoptosis. The less-studied Relm-β has similar effects. RELMs also modulate chemokine production. Our data suggest that Relm-β contributes to pathogenic upregulation of CXCL10 and CXCL11, both IFNγ-inducible CXCR3 ligands. These are known players in angiogenic disorders and have been associated with PH. Under hypoxia, mice did exhibit increased pulmonary expression of CXCL11 in a pilot study. In vitro chemokine levels indicate that RELMs stimulate CXCL10 and CXCL11 release by activated monocytic THP1 cells. Because chemokines may locally affect VSMC proliferation, cause EC apoptosis, and attract T cells that exacerbate inflammation, we hypothesize that CXCR3-driven vascular remodeling contributes to the pathogenic role of RELMs in PH. While the receptor remains unknown, our preliminary data suggest Relm-β-induced inhibition of PPARγ activity to regulate chemokine release. Our endeavors continue to unravel the receptor and downstream pathways involved. As development of RELM-targeted therapies progresses, understanding the full range of biological activities of, not only Retn, but also Relm-β, remains crucial. CXCR3 ligands have the potential to serve as valuable biomarkers as we evaluate the efficiency of innovative therapies in the field of PH.