Frataxin and endothelial cell senescence in pulmonary hypertension

Abstract

Pulmonary hypertension (PH), increased blood pressure within the lungs, is classified into five diagnostic groups based on etiology, with treatment assigned on this basis. Currently, only Group 1 pulmonary arterial hypertension (PAH) and Group 4 chronic thromboembolic PH (CTEPH) have pharmacological treatments available. The role of the endothelial cell in pulmonary hypertension has long been debated, and in this issue of the JCI, Culley et al. present evidence for the reduction in frataxin expression across multiple groups of PH. Reduced frataxin expression led to endothelial cell senescence and associated with the development of PH. Removal of the senescent cells using the senolytic drug Navitoclax in multiple models of PH effectively treated PH, suggesting a new class of treatments that may work beyond Group 1 and Group 4 PH in patients with evidence of pulmonary vascular endothelial senescence.

Figure 1. Model for precision medicine approaches to treating PH.

Reduced endothelial cell frataxin levels caused by mutations or age-associated changes in telomere length, mitochondrial function, DNA damage, and the epigenome, can induce senescence. Accumulated endothelial cells exhibiting a prooxidant SASP release proinflammatory, profibrotic, and prosenescence factors that can remodel the pulmonary vascular and result in PH. Clinicians may screen patient biopsies for senescent endothelial cells by staining with β-galactosidase and determining p16^INKA protein levels. Senolytic agents could potentially remove senescent cells, restore endothelial cell function, and normalize the pulmonary vascular bed.