Ferroptosis Promotes Pulmonary Hypertension.

ABSTRACT: The accumulation of iron-dependent lipid peroxides induces ferroptosis, a nonapoptotic form of cell death that integrates metabolic derangements with oxidative stress¹. Multiple organelles regulate ferroptosis, but the mitochondria may be the most important organelle as mitochondria both initiate and propagate ferroptosis¹. Altered ferroptosis homeostasis is linked to multiple diseases including cancer, sepsis, cardiovascular diseases, and aging. In the cardiovascular realm, ferroptosis underlies mitochondrial dysfunction and impaired cardiac contractility due to both ischemic and non-ischemic insults¹. Additionally, ferroptosis induces endothelial cell dysfunction and accelerates atherosclerosis development in mice². At present, the role of ferroptosis in the pulmonary vasculature is relatively unexplored. However, pulmonary arterial endothelial cell dysfunction, characterized by disrupted mitochondrial function and impaired iron and lipid metabolism⁴, contributes to pulmonary hypertension (PH) pathobiology. These molecular phenotypes provide a plausible link between pulmonary vascular disease and ferroptosis. Additionally, ferroptosis inhibition, starting before administration of monocrotaline (MCT), blunts PH severity in rats³, but the preventative approach used in this study may limit its translatability. Here, we employed a drug intervention in translational rodent studies, quantitative lung proteomics, and a human genetic association study to evaluate how ferroptosis modulates PH severity.

SUBMITTER: Vogel NT 

PROVIDER: S-EPMC9882268 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature