A new perspective on targeting pulmonary arterial hypertension: Programmed cell death pathways (Autophagy, Pyroptosis, Ferroptosis).

Abstract

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by elevated pulmonary vascular resistance, progressive increases in pulmonary artery pressures, ultimately leading to right-sided heart failure, and potentially mortality. Pulmonary vascular remodeling is pivotal in PAH onset and progression. While targeted drug therapies have notably ameliorated PAH prognosis, current medications primarily focus on vascular vasodilation, with limited ability to reverse pulmonary vascular remodeling fundamentally, resulting in suboptimal patient prognoses. Cellular death in pulmonary vasculature, once thought to be confined to apoptosis and necrosis, has evolved with the identification of pyroptosis, autophagy, and ferroptosis, revealing their association with vascular injury in PAH. These novel forms of regulated cellular death impact reactive oxygen species (ROS) generation, calcium stress, and inflammatory cascades, leading to pulmonary vascular cell loss, exacerbating vascular injury, and mediating adverse remodeling, inflammation, immune anomalies, and current emerging mechanisms (such as endothelial-mesenchymal transition, abnormal energy metabolism, and epigenetic regulation) in the pathogenesis of PAH. This review comprehensively delineates the roles of autophagy, pyroptosis, and ferroptosis in PAH, elucidating recent advances in their involvement and regulation of vascular injury. It juxtaposes their distinct functions in PAH and discusses the interplay of these programmed cell deaths in pulmonary vascular injury, highlighting the benefits of combined targeted therapies in mitigating pulmonary arterial hypertension-induced vascular injury, providing novel insights into targeted treatments for pulmonary arterial hypertension.