{
  "abstract": "Background Pulmonary arterial hypertension (PAH) is a progressive disease marked by elevated pulmonary artery pressure, which ultimately leads to right ventricular (RV) failure. Despite the RV being central to patient prognosis, targeted therapies are lacking. Mitochondrial dysfunction and fibroblast activation have emerged as key contributors to RV maladaptation. Moreover, sex-based differences in RV function and treatment response are increasingly recognised, yet underexplored at the cellular level. This study investigated how inhibition of nuclear factor-erythroid-derived-2-like 2 (NFE2L2), a key regulator of antioxidant response, and oestrogen signalling influence mitochondrial function in human cardiac fibroblasts under hypoxic stress, with attention to sex-specific effects.Methods Primary human male and female cardiac fibroblasts were exposed to normoxic (21% O 2) or hypoxic (1% O2) conditions and treated with vehicle (DMSO), ML385 (NFE2L2 inhibitor), 17β-estradiol (E2), or both. Mitochondrial function was assessed via live-cell confocal imaging to measure mitochondrial ROS, membrane potential, and morphology. Immunofluorescence was used to evaluate antioxidant, fibrotic, and mitochondrial markers.Results ML385 impaired mitochondrial function by increasing ROS, decreasing membrane potential, and promoting mitochondrial fragmentation under both oxygen conditions in both sexes. E2 improved mitochondrial morphology and preserved function under hypoxia, especially in female fibroblasts. Co-treatment with ML385 and E2 showed partial protection. ML385 downregulated NFE2L2 and TFAM and promoted fibrotic marker expression, while E2 reversed these effects under hypoxia.Conclusions These findings highlight sex-specific mitochondrial responses in cardiac fibroblasts and suggest that oestrogen may offer protective effects under hypoxic stress. This supports future exploration of sex-tailored, mitochondria-targeted therapies to mitigate RV dysfunction in PAH.",
  "authors": [
    {
      "affiliations": [
        "Strathclyde Institute of Pharmacy and Biomedical Sciences, The University of Strathclyde, 161 Cathedral St, Glasgow"
      ],
      "name": "Taryn Wilson"
    },
    {
      "affiliations": [
        "Strathclyde Institute of Pharmacy and Biomedical Sciences, The University of Strathclyde, 161 Cathedral St, Glasgow"
      ],
      "name": "Lian Tian"
    }
  ],
  "title": "P15  Oestrogen and NFE2L2 signalling drive sex-specific mitochondrial responses in cardiac fibroblasts with implications for RV failure in PAH",
  "uid": "a16279dd-c54d-5b52-b7ad-bc5f63b14595"
}