The Roles of S100A4 and the EGF/EGFR Signaling Axis in Pulmonary Hypertension with Right Ventricular Hypertrophy

SIMPLE SUMMARY: Pulmonary hypertension (PH) is a condition characterized by increased pulmonary arterial pressure. PH can further lead to right ventricular hypertrophy (RVH) and, consequently, heart failure. Endothelial-to-mesenchymal transition (EndMT) was identified as a key process in PH pathology. Nonetheless, the exact systemic and local levels of EndMT factors have not been comprehensively studied so far. Here, we quantified S100A4, epidermal growth factor (EGF), and EGF receptor (EGFR) in serum and tissue samples of two classes of PH with RVH. Patients with left heart disease and healthy volunteers served as controls. Serum S100A4 was decreased in the PH groups investigated, while EGF levels were increased in one PH cohort. EGFR was diminished in all groups compared to healthy controls. Surgical treatment of PH showed no effect on systemic EndMT marker levels. Furthermore, we observed a positive correlation between advanced PH stages and S100A4. Together, these findings help to deepen our understanding of the complex molecular events contributing to PH pathology and disease progression. ABSTRACT: Pulmonary hypertension (PH) is characterized by increased pulmonary arterial pressure caused by the accumulation of mesenchymal-like cells in the pulmonary vasculature. PH can lead to right ventricular hypertrophy (RVH) and, ultimately, heart failure and death. In PH etiology, endothelial-to-mesenchymal transition (EndMT) has emerged as a critical process governing the conversion of endothelial cells into mesenchymal cells, and S100A4, EGF, and EGFR are implicated in EndMT. However, a potential role of S100A4, EGF, and EGFR in PH has to date not been elucidated. We therefore quantified S100A4, EGF, and EGFR in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH). To determine specificity for unilateral heart disease, the EndMT biomarker signature was further compared between PH patients presenting with RVH and patients suffering from aortic valve stenosis (AVS) with left ventricular hypertrophy. Reduced S100A4 concentrations were found in CTEPH and iPAH patients with RVH. Systemic EGF was increased in CTEPH but not in iPAH, while AVS patients displayed slightly diminished EGF levels. EGFR was downregulated in all patient groups when compared to healthy controls. Longitudinal data analysis revealed no effect of surgical therapies on EndMT markers. Pulmonary thrombo-endarterectomized samples were devoid of S100A4, while S100A4 tissue expression positively correlated with higher grades of Heath–Edwards histopathological lesions of iPAH-derived lung tissue. Histologically, EGFR was not detectable in CTEPH lungs or in iPAH lesions. Together, our data suggest an intricate role for S100A4 and EGF/EGFR in PH with right heart pathology.