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

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-03-04 DOI:10.1016/j.bbadis.2025.167768

Jing Zhang , Xiaohan Qin , Yuhan Qin , Feng Qi , Yufei Wang , Jiameng Sun , Li Yan , Wei Sun , Xiaoxiao Guo

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引用次数: 0

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.