Ferroptosis Integrates Mitochondrial Derangements and Pathological Inflammation to Promote Pulmonary Hypertension.

Autor:	Kazmirczak F; Minneapolis Heart Institute, Minneapolis, MN., Vogel NT; Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN., Prisco SZ; Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN., Patterson MT; Center for Immunology, University of Minnesota, Minneapolis, Minnesota., Annis J; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Moon RT; Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN., Hartweck LM; Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN., Mendelson JB; Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN., Kim M; Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN., Mancipe NC; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN., Markowski T; Center for Metabolomics and Proteomics, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota., Higgins L; Center for Metabolomics and Proteomics, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota., Guerrero C; Center for Metabolomics and Proteomics, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota., Kremer B; Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN., Blake ML; Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN., Rhodes CJ; National Heart and Lung Institute, Imperial College, London, UK., Williams JW; Center for Immunology, University of Minnesota, Minneapolis, Minnesota.; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota., Brittain EL; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Prins KW; Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 23. Date of Electronic Publication: 2024 Sep 23.
DOI:	10.1101/2023.01.19.524721
Abstrakt:	Background: Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species (ROS) generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells (PAEC) exhibit cellular phenotypes that promote ferroptosis. Moreover, there is ectopic complement deposition and inflammatory macrophage accumulation in the pulmonary vasculature. However, the effects of ferroptosis inhibition on these pathogenic mechanisms and the cellular landscape of the pulmonary vasculature are incompletely defined. Methods: Multi-omics and physiological analyses evaluated how ferroptosis inhibition modulated preclinical PAH. The impact of AAV1-mediated expression of the pro-ferroptotic protein ACSL4 on PAH was determined, and a genetic association study in humans further probed the relationship between ferroptosis and pulmonary hypertension (PH). Results: Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity in monocrotaline rats. RNA-seq and proteomics analyses demonstrated ferroptosis was associated with PAH severity. RNA-seq, proteomics, and confocal microscopy revealed complement activation and pro-inflammatory cytokines/chemokines were suppressed by ferrostatin-1. Additionally, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundance and gene activation patterns as revealed by deconvolution RNA-seq. Ferroptotic PAEC damage associated molecular patterns restructured the transcriptomic signature, mitochondrial morphology, and promoted proliferation of pulmonary artery smooth muscle cells, and created a pro-inflammatory phenotype in monocytes in vitro . AAV1- Acsl4 induced an inflammatory PAH phenotype in rats. Finally, single-nucleotide polymorphisms in six ferroptosis genes identified a potential link between ferroptosis and PH severity in the Vanderbilt BioVU repository. Conclusions: Ferroptosis promotes PAH through metabolic and inflammatory mechanisms in the pulmonary vasculature.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu