Ferroptosis-Mediated Inflammation Promotes Pulmonary Hypertension

Area of Science:

• Cell Biology
• Biochemistry
• Pathology

Background:

• Mitochondrial dysfunction impairs lipid metabolism, leading to lipid peroxidation and ferroptosis, an inflammatory cell death.
• Ferroptosis promotes complement activation and macrophage recruitment, contributing to pulmonary arterial hypertension (PAH) pathogenesis.
• Pulmonary arterial endothelial cells in PAH exhibit ferroptosis-promoting phenotypes, with ectopic complement deposition and inflammatory macrophages in the pulmonary vasculature.

Purpose of the Study:

• To investigate the effects of ferroptosis inhibition on pathogenic mechanisms in preclinical pulmonary arterial hypertension (PAH).
• To evaluate the impact of modulating ferroptosis on the cellular landscape of the pulmonary vasculature in PAH.
• To explore the relationship between ferroptosis and pulmonary hypertension severity in human genetic studies.

Main Methods:

• Multiomics (RNA-sequencing, proteomics) and physiological analyses were used to assess ferroptosis inhibition in preclinical PAH models.
• Adeno-associated virus 1-mediated expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) was used to study ferroptosis induction.
• Genetic association studies using single-nucleotide polymorphisms in ferroptosis genes were conducted in the Vanderbilt BioVU repository.

Main Results:

• Ferrostatin-1, a ferroptosis inhibitor, mitigated PAH severity in monocrotaline-induced rat models.
• RNA-sequencing and proteomics confirmed ferroptosis association with PAH severity and showed Ferrostatin-1 suppressed complement activation and proinflammatory cytokines.
• Ferrostatin-1 treatment reversed changes in endothelial, smooth muscle, and macrophage populations and gene expression in PAH models.
• In vitro studies demonstrated ferroptotic cell damage-associated molecular patterns promoted smooth muscle cell proliferation and monocyte inflammation.
• ACSL4 induction promoted an inflammatory PAH phenotype in rats.
• Human genetic analysis revealed a potential link between ferroptosis gene polymorphisms and PAH severity.

Conclusions:

• Ferroptosis significantly contributes to pulmonary arterial hypertension (PAH) through metabolic and inflammatory pathways within the pulmonary vasculature.
• Inhibition of ferroptosis presents a potential therapeutic strategy for mitigating PAH progression and its associated inflammatory complications.