BACKGROUND Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species 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 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 Multiomics and physiological analyses evaluated how ferroptosis inhibition-modulated preclinical PAH. The impact of adeno-associated virus 1-mediated expression of the proferroptotic protein ACSL (acyl-CoA synthetase long-chain family member) 4 on PAH was determined, and a genetic association study in humans further probed the relationship between ferroptosis and pulmonary hypertension. RESULTS Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity in monocrotaline rats. RNA-sequencing and proteomics analyses demonstrated ferroptosis was associated with PAH severity. RNA-sequencing, proteomics, and confocal microscopy revealed complement activation and proinflammatory cytokines/chemokines were suppressed by ferrostatin-1. In addition, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundance and gene activation patterns as revealed by deconvolution RNA-sequencing. Ferroptotic pulmonary arterial endothelial cell damage-associated molecular patterns restructured the transcriptomic signature and mitochondrial morphology, promoted the proliferation of pulmonary artery smooth muscle cells, and created a proinflammatory phenotype in monocytes in vitro. Adeno-associated virus 1-Acsl4 induced an inflammatory PAH phenotype in rats. Finally, single-nucleotide polymorphisms in 6 ferroptosis genes identified a potential link between ferroptosis and pulmonary hypertension severity in the Vanderbilt BioVU repository. CONCLUSIONS Ferroptosis promotes PAH through metabolic and inflammatory mechanisms in the pulmonary vasculature.

中文翻译：

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铁死亡介导的炎症会促进肺动脉高压。


背景 线粒体功能障碍，以脂质代谢受损和活性氧生成增加为特征，导致脂质过氧化和铁死亡。铁死亡是一种细胞死亡的炎症模式，可促进补体激活和巨噬细胞募集。在肺动脉高压 （PAH） 中，肺动脉内皮细胞表现出促进铁死亡的细胞表型。此外，肺血管系统中存在异位补体沉积和炎性巨噬细胞积累。然而，铁死亡抑制对这些致病机制和肺血管系统细胞景观的影响尚不完全明确。方法 多组学和生理学分析评估了铁死亡抑制如何调节临床前 PAH。确定了腺相关病毒 1 介导的铁死亡蛋白 ACSL （酰基辅酶 A 合成酶长链家族成员） 4 表达对 PAH 的影响，一项人类遗传关联研究进一步探讨了铁死亡与肺动脉高压之间的关系。结果 Ferrostatin-1 是一种小分子铁死亡抑制剂，可减轻野百合碱大鼠的 PAH 严重程度。RNA 测序和蛋白质组学分析表明，铁死亡与 PAH 严重程度相关。RNA 测序、蛋白质组学和共聚焦显微镜检查显示，ferrostatin-1 抑制了补体激活和促炎细胞因子/趋化因子。此外，铁司他汀-1 对抗反卷积 RNA 测序揭示的内皮、平滑肌和间质巨噬细胞丰度以及基因激活模式的变化。 铁死亡肺动脉内皮细胞损伤相关分子模式重构了转录组特征和线粒体形态，促进了肺动脉平滑肌细胞的增殖，并在体外单核细胞中创造了促炎表型。腺相关病毒 1-Acsl4 诱导大鼠炎性 PAH 表型。最后，在 Vanderbilt BioVU 存储库中，6 个铁死亡基因中的单核苷酸多态性确定了铁死亡与肺动脉高压严重程度之间的潜在联系。结论 铁死亡通过肺血管系统中的代谢和炎症机制促进 PAH。