Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension.

Vascular inflammation regulates endothelial pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulated lysosomal activity and cholesterol metabolism activate pathogenic inflammation, but their relevance to PAH is unclear. Nuclear receptor coactivator 7 () deficiency in endothelium produced an oxysterol and bile acid signature through lysosomal dysregulation, promoting endothelial pathophenotypes.

Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function.

Deficiency of iron‑sulfur (FeS) clusters promotes metabolic rewiring of the endothelium and the development of pulmonary hypertension (PH) in vivo. Joining a growing number of FeS biogenesis proteins critical to pulmonary endothelial function, recent data highlighted that frataxin (FXN) reduction drives Fe-S-dependent genotoxic stress and senescence across multiple types of pulmonary vascular disease. Trinucleotide repeat mutations in the FXN gene cause Friedreich's ataxia, a disease characterized by cardiomyopathy and neurodegeneration.

Frataxin deficiency promotes endothelial senescence in pulmonary hypertension.

The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence.

The molecular rationale for therapeutic targeting of glutamine metabolism in pulmonary hypertension.

Pulmonary hypertension (PH) is a deadly enigmatic disease with increasing prevalence. Cellular pathologic hallmarks of PH are driven at least partly by metabolic rewiring, but details are just emerging. The discovery that vascular matrix stiffening can mechanically activate the glutaminase (GLS) enzyme and serve as a pathogenic mechanism of PH has advanced our understanding of the complex role of glutamine in PH.

Rethinking the Paradigm: Modern Approach to Proximal Aortic Reconstruction Demonstrates Excellent Outcomes.

Background: Techniques for aortic surgery continue to evolve. A real-world snapshot of patients undergoing elective surgery for aneurysm in the modern era is helpful to assist in deciding the appropriate timing for intervention. We herein describe our experience with 100 consecutive patients who underwent primary elective surgery for aneurysm of the proximal thoracic aorta over a two-year period at a single institution.