Abstract Rationale Pulmonary arterial hypertension (PAH) is a progressive disease marked by elevated pulmonary vascular resistance and right heart failure. Current therapies are largely palliative, highlighting the need to identify novel molecular drivers. Dermcidin (DCD), a stress-response and antimicrobial protein, drives inflammation, oxidative stress, and cellular proliferation, and has been implicated in cardiomyocyte injury and tumor progression, including lung cancer, suggesting a potential role in PAH pathogenesis. Methods Membrane-based proteomics using quantitative Mass spectrometry (LC MS/MS) was performed on pulmonary artery smooth muscle cells (PASMCs) isolated from patients with idiopathic PAH (IPAH) and healthy controls. Candidate proteins were validated at transcript and protein levels in PASMCs and lung homogenates using quantitative PCR and immunoblotting. Circulating DCD levels were measured by ELISA in plasma samples from male and female PAH patients and correlated with clinical parameters, including cardiac index. To evaluate DCD’s functional role, PASMCs were treated with the small-molecule inhibitor seriniquinone (SQ) at 1, 5, and 10 µM, and proliferation and apoptosis were assessed using BrdU incorporation and nucleosome-based apoptosis assays (Roche). Mechanistic studies examined MAPK/STAT signaling and cell cycle/apoptotic markers by immunoblotting. Results Proteomic profiling identified Dermcidin (DCD) as significantly upregulated in PASMCs from IPAH patients. This upregulation was confirmed at both transcript and protein levels in IPAH PASMCs and in lung homogenates from a monocrotaline-induced PAH rat model. Plasma DCD levels were elevated in male PAH patients and inversely correlated with cardiac index, suggesting a potential sex-specific biomarker association. Pharmacological inhibition of DCD with SQ significantly suppressed PASMC proliferation and induced dose-dependent apoptosis. Mechanistic analyses revealed that SQ treatment attenuated phosphorylation of ERK and STAT3 and downregulated Cyclin D1 expression, indicating that DCD mediates PASMC growth and survival through the ERK/STAT signaling pathway. Conclusions These results suggest that Dermcidin plays a key role in disease progression and represents a potential therapeutic target in pulmonary arterial hypertension. This abstract is funded by: none
Veeroju et al. (Fri,) studied this question.