Proteomic- and metabolomic-based mechanisms of androgen-mediated right ventricular maladaptive remodeling under...

Right ventricular (RV) maladaptive remodeling has been demonstrated to be more severe in males than in females under similar afterload, with androgen potentially involved. However, the mechanism remains unknown.

We performed RV proteomics and metabolomics in male and castrated rats with pulmonary artery banding (PAB) or sham surgery. The core pathway was tested in other sets of male, castrated male, and testosterone-replaced rats with and without pathway inhibitors administration and in RV remodeling patients. Metabolite verification was carried out by matching secondary spectra.

With the same extent of increases in RV afterload, male PAB rats exhibited more pronounced RV hypertrophy and fibrosis than castrated PAB rats (p < 0.05). The omics analysis indicated that pathways and functions related to oxidative stress were exhibited in the male group, with the platelet-derived growth factor (PDGF) pathway being among them. More proteins and metabolites associated with fatty acid metabolism were downregulated in males. Correlation analysis showed that PDGF receptor beta (PDGFRB) and signal transducer and activator of transcription 3 (STAT3) were negatively correlated with carnitine and reactive oxygen species scavenging metabolites only in male rats. The activation of the PDGF pathway was verified in testosterone-replaced PAB rats and male patients with RV remodeling. Treatments with PDGFRB inhibitor and STAT3 inhibitor could reverse RV maladaptive remodeling in male and testosterone-replaced PAB rats but not in castrated ones.

Androgen might exacerbate RV maladaptive remodeling via intensified oxidative stress and insufficient energy supply, with activating the PDGFRB-STAT3 signaling being one of the possible pathways.